1: Surgery. 1964 Aug;56:459-60. THE ACCELERATION OF HEALING. PRUDDEN JF. PMID: 14213848 [PubMed - indexed for MEDLINE] 2: Arch Surg. 1964 Dec;89:1046-59. WOUND HEALING PRODUCED BY CARTILAGE PREPARATIONS. THE ENHANCEMENT OF ACCELERATION, WITH A REPORT ON THE USE OF A CARTILAGE PREPARATION IN CLINICALLY CHRONIC ULCERS AND IN PRIMARILY CLOSED HUMAN SURGICAL INCISIONS. PRUDDEN JF. PMID: 14208451 [PubMed - indexed for MEDLINE] 3: Science. 1983 Sep 16;221(4616):1185-7. Shark cartilage contains inhibitors of tumor angiogenesis. Lee A, Langer R. Shark cartilage contains a substance that strongly inhibits the growth of new blood vessels toward solid tumors, thereby restricting tumor growth. The abundance of this factor in shark cartilage, in contrast to cartilage from mammalian sources, may make sharks an ideal source of the inhibitor and may help to explain the rarity of neoplasms in these animals. Publication Types: Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. PMID: 6193581 [PubMed - indexed for MEDLINE] 4: Cancer Lett. 1990 Jun 15;51(3):181-6. A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Oikawa T, Ashino-Fuse H, Shimamura M, Koide U, Iwaguchi T. Department of Cancer Therapeutics, Tokyo Metropolitan Institute of Medical Science, Japan. Guanidine extraction and crude fractionation of Japanese shark cartilage by ultrafiltration on a molecular weight basis were conducted and the antiangiogenic activities were assayed as to the inhibitions of tumor and embryonic angiogenesis. Significant inhibition of angiogenesis was found, and there was a linear relationship between the results of the two assays. The inhibitory activities were concentrated in the fraction in the molecular weight range of 103 to 104, and were resistant to heat treatment. PMID: 1693543 [PubMed - indexed for MEDLINE] 5: J Natl Cancer Inst. 1992 Jul 1;84(13):1000-2. Erratum in: J Natl Cancer Inst 1992 Aug 19;84(16):1237. Comment in: J Natl Cancer Inst. 1993 Dec 1;85(23):1961-2. Sharks still intrigue cancer researchers. Mathews J. Publication Types: News PMID: 1608049 [PubMed - indexed for MEDLINE] 6: J Natl Cancer Inst. 1993 Aug 4;85(15):1190-1. Media feeds frenzy over shark cartilage as cancer treatment. Mathews J. Publication Types: News PMID: 8331677 [PubMed - indexed for MEDLINE] 7: J Natl Cancer Inst. 1993 Dec 1;85(23):1961-2. Comment on: J Natl Cancer Inst. 1992 Jul 1;84(13):1000-2. Skeptics of oral administration of shark cartilage. Blackadar CB. Publication Types: Comment Letter PMID: 8230290 [PubMed - indexed for MEDLINE] 8: Am J Health Syst Pharm. 1995 Aug 15;52(16):1756, 1760. Shark cartilage for cancer treatment. Hunt TJ, Connelly JF. Department of Pharmacy, North Carolina Baptist Hospitals, Inc., Winston-Salem 27157, USA. PMID: 8528831 [PubMed - indexed for MEDLINE] 9: Pharmacotherapy. 1996 Mar-Apr;16(2):237-44. Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium. McGuire TR, Kazakoff PW, Hoie EB, Fienhold MA. Department of Pharmacy Practice, University of Nebraska, Omaha 68198-6045, USA. We evaluated the antiangiogenic activity of shark cartilage, tumor necrosis factor-alpha (TNF-alpha), and a combination of the two using a human umbilical vein endothelial cell proliferation assay. Proliferation of endothelium is a hallmark of angiogenesis, and inhibition of endothelial cell proliferation indicates potential antiangiogenic activity. Shark cartilage produced a concentration-dependent decline in endothelial cell 3H-thymidine incorporation. This activity was heat stable and was found in molecular weight fractions of less than 10 kd. The antiproliferative effect of shark cartilage was specific for vascular endothelium and did not affect the proliferative rate of human astrocytoma cells or human skin fibroblasts. Shark cartilage at a concentration of 500 mu g/ml and TNF-alpha at a concentration of 10 ng/ml reduced endothelial cell proliferation by 32% and 29%, respectively. Treatment of endothelial cells with the combination of shark cartilage and TNF-alpha resulted in a 44% reduction in endothelial cell proliferation. The isolation and identification of the active components of shark cartilage is continuing. PMID: 8820467 [PubMed - indexed for MEDLINE] 10: Mutat Res. 1996 Apr 6;367(4):204-8. Shark-cartilage containing preparation protects cells against hydrogen peroxide induced damage and mutagenesis. Gomes EM, Souto PR, Felzenszwalb I. CETOX-Departamento de Biofísica e Biometria, Universidade do Estado do Rio de Janeiro, Brazil. Natural products from flora and fauna are frequently used as nutritional supplements and medicaments. Two short-term assays were carried out and negative results were obtained for shark-cartilage containing preparation. The tests employed were the Salmonella/mammalian microsome assay using tester strains TA97, TA98, TA100, TA102 and TA1535 with or without S9 mix and the SOS-Chromotest with Escherichia coli strain PQ37. Evidence for shark-cartilage containing preparation functioning as an antimutagen was detected. Using bacterial survival assays with Escherichia coli fpg (BH20) and xthA (BW9091), we investigated the putative role of shark-cartilage containing preparation in protecting cells against lesions induced by hydrogen peroxide in normal and low iron level conditions. Our data suggest that shark-cartilage containing preparation can play a scavenger role for reactive oxygen species and protect against DNA lesions in both conditions. Publication Types: Research Support, Non-U.S. Gov't PMID: 8628326 [PubMed - indexed for MEDLINE] 11: Cleve Clin J Med. 1996 May-Jun;63(3):179-80. Shark cartilage: the Laetrile of the 1990s. Markman M. Publication Types: Editorial PMID: 8665657 [PubMed - indexed for MEDLINE] 12: Braz J Med Biol Res. 1996 May;29(5):643-6. Anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage. Fontenele JB, Viana GS, Xavier-Filho J, de-Alencar JW. Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil. The anti-inflammatory and analgesic activities of a water-soluble fraction (WSF), extracted with 0.1 M ammonium bicarbonate, pH 8.0, from shark cartilage were studied in several experimental models. Orally administered WSF (10 mg/kg) caused 25.7 and 23.6% inhibition of the paw edema produced in female Wistar rats (200-250 g) by carrageenan and dextran, respectively, after 3 h, as compared to controls. WSF administered orally had no effect on acetic acid-induced writhings in male Swiss mice (25-30 g) at the dose of 0.01 mg/kg but caused 52.8 and 61.4% inhibition at the doses of 0.1 and 0.5 mg/kg, respectively, compared to controls (No. of writhings/20 min, means +/- SEM: treated groups = 18.6 +/- 2.5, N = 12 and 15.2 +/- 1.4, N = 12, respectively; controls = 39.3 +/- 1.3, N = 77). In the formalin test (male Swiss mice, 25-30 g), orally administered WSF (0.5 and 1 mg/kg) caused 12.0 and 46.6% inhibition of licking time, respectively, only in the 2nd phase (inflammatory) of the test (licking time, means +/- SEM: treated group = 18.3 +/- 4.4 sec, N = 7 and 11.1 +/- 3.4 sec, N = 13; controls = 20.8 +/- 2.4 sec, N = 44). The results suggest that a molecule of a protein nature in shark cartilage is probably responsible for the effects observed. Publication Types: Research Support, Non-U.S. Gov't PMID: 9033816 [PubMed - indexed for MEDLINE] 13: Ann Intern Med. 1996 Nov 1;125(9):780-1. Shark cartilage-induced hepatitis. Ashar B, Vargo E. Publication Types: Case Reports Letter PMID: 8929024 [PubMed - indexed for MEDLINE] 14: Microvasc Res. 1997 Sep;54(2):178-82. Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Davis PF, He Y, Furneaux RH, Johnston PS, Rüger BM, Slim GC. Department of Medicine, Wellington School of Medicine, New Zealand. Publication Types: Research Support, Non-U.S. Gov't PMID: 9327389 [PubMed - indexed for MEDLINE] 15: Biol Pharm Bull. 1997 Nov;20(11):1151-4. The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent. Fontenele JB, Araújo GB, de Alencar JW, Viana GS. Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil. The present work shows an antinociceptive and dose-dependent effect of shark cartilage hydrosoluble fraction (HF) on writhing and formalin tests in mice. The effect was not altered by thalidomide, a known inhibitor of tumor necrosis factor-alfa (TNF-alfa) synthesis. Similarly, the antinociceptive effect did not change in the presence of naloxone, indicating that the opioid system is not involved. However, the effect observed was blocked by L-arginine, a NO synthesis substrate, and it was potentiated by L-NAME, suggesting a role of the NO system in the shark cartilage antinociceptive effect. Effects similar to those seen with the HF were detected with peak II from gel filtration chromatography. The increase in vascular permeability induced by serotonin in rats was significantly abolished by the HF at the dose of 2 mg/kg, p.o., and again it was not potentiated by thalidomide. The observed blockade in the vascular permeability increase induced by histamine was detected only with a higher dose (10 mg/kg, p.o.). Publication Types: Research Support, Non-U.S. Gov't PMID: 9401722 [PubMed - indexed for MEDLINE] 16: Lancet. 1998 Jan 24;351(9098):298. Comment in: Lancet. 1998 May 9;351(9113):1440. Shark cartilage for cancer? Ernst E. Publication Types: Letter PMID: 9457132 [PubMed - indexed for MEDLINE] 17: J Cutan Med Surg. 1998 Jan;2(3):146-52. Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis. Dupont E, Savard PE, Jourdain C, Juneau C, Thibodeau A, Ross N, Marenus K, Maes DH, Pelletier G, Sauder DN. Les Laboratoires Aeterna, Ste-Foy, PQ, Canada. BACKGROUND: A number of inflammatory and immune diseases are associated with vascular changes. Psoriasis, as an example, is a common inflammatory skin disease with dilation of capillaries as an early histological change. In more developed psoriatic lesions there is proliferation of blood vessels and neovascularization. The use of agents that target these vascular changes represents a novel therapeutic strategy in the treatment of inflammatory diseases. Since cartilage is an avascular tissue, it has been hypothesized that there may be factors found in cartilage that inhibit blood vessel formation. OBJECTIVE: The objectives of this study were 1) to determine whether extracts of cartilage could inhibit angiogenesis, and 2) since altered angiogenesis is associated with certain diseases, including psoriasis, to examine whether inhibition of angiogenesis could potentially contribute to the treatment of psoriasis. METHODS: Extracts of shark cartilage were prepared by homogenization and ultrafiltration to derive the active agent termed AE -941. This agent was tested for antiangiogenesis activity using the embryonic vascularization test, which is a modification of the ex vivo chick embryo culture (CAM). Since one of the first steps in angiogenesis is degradation by metalloproteinases of the basement membrane of capillaries, AE -941 was tested for collagenase activity using a fluorogenic peptide substrate. Anti-inflammatory properties were tested using a cutaneous irritation model in humans. RESULTS: A dose dependent inhibition in embryonic neovascularization as well as in collagenase activity by AE -941 was demonstrated. When test compounds were applied on the forearms of test subjects, AE -941 was shown to have anti-inflammatory properties. Anecdotal data suggested that topical AE -941 had a beneficial effect in psoriasis. CONCLUSION: Our results show that AE -941 has anti-angiogenic and anti-inflammatory properties. Antiangiogenesis agents such as AE -941 provide an entirely new class of agents to treat cutaneous and systemic diseases associated with altered vascularity. Publication Types: Research Support, Non-U.S. Gov't PMID: 9479080 [PubMed - indexed for MEDLINE] 18: Lancet. 1998 May 9;351(9113):1440. Comment on: Lancet. 1998 Jan 24;351(9098):298. Shark cartilage for cancer. Simone CB, Simone NL, Simone CB 2nd. Publication Types: Comment Letter PMID: 9593449 [PubMed - indexed for MEDLINE] 19: N Engl J Med. 1998 Sep 17;339(12):846-7. Comment in: N Engl J Med. 1998 Sep 17;339(12):839-41. N Engl J Med. 1999 Feb 18;340(7):569. N Engl J Med. 1999 Feb 18;340(7):569-70. Alternative therapies for the treatment of childhood cancer. Coppes MJ, Anderson RA, Egeler RM, Wolff JE. Publication Types: Case Reports Letter PMID: 9750078 [PubMed - indexed for MEDLINE] 20: J Clin Oncol. 1998 Nov;16(11):3649-55. Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. Miller DR, Anderson GT, Stark JJ, Granick JL, Richardson D. Cancer Treatment Research Foundation, Cancer Treatment Centers of America, Arlington Heights, IL 60005, USA. gary.anderson@ctca-corp.com PURPOSE: Patients with cancer and chronic inflammatory disorders have used shark cartilage (SC) preparations for many years. Preclinical studies that support their beneficial effects are scanty, and reports of clinical trials have been anecdotal. The proposed mechanisms of antitumor action include direct or indirect inhibition of angiogenesis. Because of the emerging use of SC as an alternative to conventional cancer therapy, this trial was launched to evaluate the safety and efficacy of SC. PATIENTS AND METHODS: Sixty adult patients with advanced previously treated cancer (breast, 16 patients; colorectal, 16 patients; lung, 14 patients; prostate, eight patients; non-Hodgkin lymphoma, three patients; brain, one patient; and unknown primary tumor, two patients) were enrolled. Eligibility criteria included confirmation of diagnosis, resistance to conventional therapy, objective measurable disease, life expectancy of 12 weeks or greater, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, no recent or concomitant anticancer therapy, no prior SC, and informed consent. Patients underwent evaluation of the extent of disease, quality-of-life score (Functional Assessment of Cancer Therapy-General [FACT-G] scale), and hematologic, biochemical, and selected immune function studies at baseline and after 6 and 12 weeks of SC therapy. The dose of SC was 1 g/kg daily orally in three divided doses. Standard criteria were used to evaluate adverse events and response. RESULTS: Ten of 60 patients were lost to follow-up(LTFU) or refused further treatment (RFT) before the 6-week evaluation and were not assessable for toxicity and response. Three patients with stable disease at 6 weeks were LTFU or RFT thereafter. Of the 47 fully assessable patients, five were taken off study because of gastrointestinal toxicity or intolerance to SC. Progressive disease (PD) at 6 or 12 weeks occurred in 22 and five patients, respectively. Five patients died of PD while undergoing SC therapy. No complete (CRs) or partial responses (PRs) were noted. Median time to tumor progression in the entire study population was 7+/-9.7 weeks (mean, 11.4 weeks; range, 3.7 to 45.7 weeks). Ten (20%) of 50 assessable patients, or 16.7% of the 60 intent-to-treat patients, had stable disease (SD) for 12 weeks or more. The median time to tumor progression was 27 weeks, the mean was 28.8+/-9.9 weeks, and the range was 18.6 to 45.7 weeks. In this subset, FACT-G scores improved in four patients, were unchanged in four patients, and declined in two patients. Twenty-one adverse events (grade 1, eight events; grade 2, seven events; and grade 3, six events) were recorded, 14 of which were gastroenterologic (nausea, vomiting, constipation). CONCLUSION: Under the specific conditions of this study, SC as a single agent was inactive in patients with advanced-stage cancer and had no salutary effect on quality of life. The 16.7% rate of SD was similar to results in patients with advanced cancer treated with supportive care alone. Publication Types: Clinical Trial Clinical Trial, Phase I Clinical Trial, Phase II Research Support, Non-U.S. Gov't PMID: 9817287 [PubMed - indexed for MEDLINE] 21: Acta Oncol. 1998;37(5):441-5. The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma. Horsman MR, Alsner J, Overgaard J. Danish Cancer Society, Department of Experimental Clinical Oncology, Aarhus University Hospital. This study was designed to investigate the potential of shark cartilage extracts to inhibit the growth and metastatic spread of a murine solid tumour. The SCCVII carcinoma, implanted in the right rear foot of C3H mice, was used. Following tumour implantation, two different commercially available extracts of shark cartilage (Sharkilage and MIA Shark Powder) were dissolved in water and orally administered to the mice at doses that ranged from 5 to 100 mg per mouse. These injections were repeated on a daily basis for up to 25 days post-implantation of the primary tumour. Compared to non-drug-treated animals, daily administration of the shark cartilage extracts did not show any adverse toxicity (as measured by changes in body weight and lethality). More importantly, none of the shark cartilage doses tested had any retarding effect on the growth of the primary tumour, nor did they inhibit the development of metastases seen in the lungs of the tumour-bearing mice at autopsy. In conclusion, our results offer no support for the proposed use of shark cartilage extracts as an anti-cancer therapy. Publication Types: Research Support, Non-U.S. Gov't PMID: 9831372 [PubMed - indexed for MEDLINE] 22: Food Chem Toxicol. 1998 Dec;36(12):1079-84. Shark cartilage-containing preparation: protection against reactive oxygen species. Felzenszwalb I, Pelielo de Mattos JC, Bernardo-Filho M, Caldeira-de-Araújo A. Universidade do Estado do, Rio de Janeiro, Instituto de Biologia, Departamento de Biofísica e Biometria, Brazil. There is overwhelming evidence to indicate that free radicals cause oxidative damage to lipids, proteins and nucleic acids and are involved in the pathogenesis of several degenerative diseases. Therefore, antioxidants, which can neutralize free radicals, may be of central importance in the prevention of these disease states. The protection that fruits and vegetables provide against disease has been attributed to the various antioxidants contained in them. Recently, an anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage has been described. Using electrophoretical assays, bacteria survival and transformation and the Salmonella/mammalian-microsome assay, we investigated the putative role of shark cartilage-containing preparation in protecting cells against reactive oxygen species induced DNA damage and mutagenesis. If antimutagens are to have any impact on human disease, it is essential that they are specifically directed against the most common mutagens in daily life. Our data suggest that shark cartilage-containing preparation can play a scavenger role for reactive oxygen species and protects cells against inactivation and mutagenesis. Publication Types: Research Support, Non-U.S. Gov't PMID: 9862650 [PubMed - indexed for MEDLINE] 23: Anticancer Res. 1998 Nov-Dec;18(6A):4435-41. Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities. Sheu JR, Fu CC, Tsai ML, Chung WJ. Cancer Research Center, Gwo-Chyang GMP Pharmaceutical Co., Ltd., Tainan, Taiwan. acesane@ms4.hinet.net BACKGROUND: A potent angiogenesis inhibitor, U-995, has been purified from the cartilage of the blue shark (Prionace glauca). U-995 is composed of two single peptides with molecular mass of 10 and 14 kDa, respectively. MATERIALS AND METHODS: U-995 was designed to study human umbilical vein endothelial cell (HUVEC) migration and proliferation in vitro and angiogenesis induced by TNF alpha in chicken chorioallantoic membrane (CAM). Furthermore, we determined the ability of U-995 to inhibiting tumor cell growth and metastasis. RESULTS: U-995 (15 and 30 micrograms/ml) markedly inhibited HUVEC migration and, at 15-50 micrograms/ml produced a dose-dependent decline in [3H]-thymidine incorporation. 30 and 50 micrograms/ml of U-995, when added to TNF alpha-induced angiogenesis caused discontinuous and disrupted blood vessels. Moreover, U-995 (30 micrograms/ml) markedly prevented collagenase-induced collagenolysis. In addition, when 200 micrograms U-995 was injected i.p. into mice it suppressed sarcoma-180 cell growth and B16-F10 mouse melanoma cell metastasis in vivo. CONCLUSIONS: These results suggest that the anti-angiogenic effects of U-995 may be be due to interference with the proliferation and migration of HUVECs as well as inhibition of collagenolysis, thereby leading to inhibition of both angiogenesis and tumor cell growth. Publication Types: Research Support, Non-U.S. Gov't PMID: 9891506 [PubMed - indexed for MEDLINE] 24: J Palliat Care. 1998 Winter;14(4):21-6. The use of complementary medications by cancer patients attending an outpatient pain and symptom clinic. Oneschuk D, Fennell L, Hanson J, Bruera E. Cross Cancer Institute, Edmonton, Alberta, Canada. Complementary medications appear to be gaining popularity among cancer patients. When we surveyed 143 advanced cancer patients attending an outpatient pain and symptom clinic at a regional cancer centre as to their use of complementary medications and nutritional supplements, we found 37% (53/143) to be making use of complementary medications. Users tended to be younger (mean age 53.3 years) and have a preference for purchase from health stores, with 61% of complementary medications being bought there. Health store staff were the primary recommenders for both men and women and especially for those over 60 years of age. Of the 197 complementary medications purchased, 78 (39.6%) were herbs, 67 (32.5%) were vitamins, 13 (6.6%) were minerals, 21 (10.7%) were other medications including shark cartilage, and 21 (10.7%) could not be identified. Both anticancer effect and the promotion of well-being were prominent among the stated reasons for using these medications. PMID: 9893394 [PubMed - indexed for MEDLINE] 25: Oncology (Williston Park). 1999 Jan;13(1):82. NCI to sponsor phase III trials of liquid shark cartilage angiogenesis inhibitor. [No authors listed] Publication Types: Comparative Study News PMID: 10223792 [PubMed - indexed for MEDLINE] 26: Ned Tijdschr Geneeskd. 1999 Jul 3;143(27):1431-3. Comment in: Ned Tijdschr Geneeskd. 1999 Aug 7;143(32):1680. Ned Tijdschr Geneeskd. 1999 Jul 17;143(29):1542-3. Ned Tijdschr Geneeskd. 1999 Oct 9;143(41):2073-4; author reply 2076-7. Ned Tijdschr Geneeskd. 1999 Oct 9;143(41):2074-5. Ned Tijdschr Geneeskd. 1999 Oct 9;143(41):2074-6. [The national cancer fund (Koningin Wilhelmina Fonds) and the Houtsmuller-therapy for cancer] [Article in Dutch] Renckens CN, van Dam FS. Nederlands Kanker Instituut/Antoni van Leeuwenhoek ziekenhuis, afd. Psychosociaal Onderzoek en Epidemiologie, Amsterdam. Dr. Houtsmuller, a retired internist, introduced an anticancer diet ten years ago. He claimed to have cured himself from metastatic melanoma by following a diet consisting of healthy nutrients, large amounts of vitamins, minerals, antioxidants and shark cartilage powder in combination with psychological support. The efficacy of the therapy was never described in a scientific article. Currently about 63% of all cancer patients in the Netherlands using a diet use the Houtsmuller diet. The national cancer fund (Koningin Wilhelmina Fonds) invited him to speak at their 50-year commemorative symposium. Shortly before he admitted that his medical history did not mention metastatic melanoma. Dr. Houtsmuller has seriously damaged the position of physicians in the Netherlands by addressing patients directly without first seeking support from his scientific medical peers. Cancer organizations such as Koningin Wilhelmina Fonds are urged to properly inform the public about the real value or lack of value of alternative treatments in general and of alternative diets in particular. Publication Types: English Abstract Letter PMID: 10422559 [PubMed - indexed for MEDLINE] 27: J Surg Res. 1999 Nov;87(1):108-13. Erratum in: J Surg Res 2000 Apr;89(2):197. El-Khouri S [corrected to Elkouri S]. Antiangiogenic effects of the oral administration of liquid cartilage extract in humans. Berbari P, Thibodeau A, Germain L, Saint-Cyr M, Gaudreau P, Elkhouri S, Dupont E, Garrel DR, Elkouri S. Hôtel-Dieu Hospital, University of Montreal Medical School, Montreal, Canada. BACKGROUND: The antiangiogenic properties of shark cartilage extracts have been demonstrated in animal models but there are no data in human subjects. MATERIALS AND METHODS: A placebo or one of two doses of a liquid shark cartilage extract was orally administered daily, from Day 1 to Day 23 of the study protocol, to 29 healthy male volunteers randomized into three groups. On Day 12, a polyvinyl alcohol sponge threaded in a perforated silicone tubing was inserted subcutaneously on the anterior side of the arm and removed on Day 23. Evaluation of endothelial cell density, with factor VIII immunostaining, an indirect measurement of angiogenesis, was performed on histological sections of the implant using a semiquantitative numerical scale ranging from 1 (low density) to 5 (high density). The hydroxyproline content of the sponges was measured by HPLC. RESULTS: The mean endothelial cell density was significantly lower in groups that had received the liquid cartilage extract: grades 2.24 +/- 0.10, 2.47 +/- 0.10, and 3.15 +/- 0.11 for 7 and 21 ml liquid cartilage extract and placebo, respectively (P < 0.01 for both comparisons). No grade 1 was observed in the placebo group, whereas 9 treated subjects received a grade 1. Hydroxyproline content of the sponges did not differ between groups and there was no significant correlation between hydroxyproline content and endothelial cell density in the sponges. CONCLUSIONS: These results demonstrate that the liquid cartilage extract contains an antiangiogenic component bioavailable in humans by oral administration. This is the first report of an inhibition of wound angiogenesis in healthy men. Copyright 1999 Academic Press. Publication Types: Clinical Trial Randomized Controlled Trial PMID: 10527711 [PubMed - indexed for MEDLINE] 28: Eur J Cancer. 1999 Oct;35(11):1608-13. How useful are unconventional cancer treatments? Ernst E, Cassileth BR. Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, U.K. e.ernst@exeter.ac.uk Unconventional cancer treatments are used frequently. Therefore, oncologists need to know about them. This article gives an overview of current knowledge on the most prevalent complementary or alternative cancer therapies. A distinction is made between alleged cures, preventive and adjunctive measures. Shark cartilage, mistletoe, thymus therapy, essiac, hydrazine sulphate, 714-X, dietary regimens, green tea and Panax ginseng are all covered specifically. None of these treatments offer reasonable hope for a cure. Some strategies are promising in terms of cancer prevention. The true potential of unconventional therapies might lie in adjunctive and palliative care. It is concluded that good evidence in this area is scarce. Vis-à-vis the high prevalence of unconventional cancer treatments, rigorous investigations are mandatory, not least for increasing the safety of future patients. Publication Types: Review PMID: 10673970 [PubMed - indexed for MEDLINE] 29: Schweiz Med Wochenschr. 1999 Dec 28;129(51-52):1996-7. [Shark cartilage on the Internet] [Article in German] Steurer J. Medizinische Poliklinik, Universitätsspital, Zürich. www.evimed.ch PMID: 10674306 [PubMed - indexed for MEDLINE] 30: Br J Radiol. 2000 Apr;73(868):429-34. Boron neutron capture therapy of the rat 9L gliosarcoma: evaluation of the effects of shark cartilage. Morris GM, Coderre JA, Micca PL, Lombardo DT, Hopewell JW. Research Institute (University of Oxford), Churchill Hospital, UK. A number of anti-angiogenic substances are now under evaluation, both experimentally and clinically, as potential agents for the treatment of cancer. It has recently been demonstrated that anti-angiogenic agents can increase the therapeutic potential of photon irradiation in a range of tumour models. In the present communication a preliminary assessment is made of the effects of shark cartilage on the response of the rat 9L gliosarcoma to boron neutron capture therapy (BNCT). Shark cartilage was administered orally as an aqueous suspension at a daily dose of approximately 2000 mg kg-1 body weight. The mean survival time of rats receiving no treatment was 20.7 +/- 0.5 days post intracranial tumour implantation. Administration of shark cartilage alone extended the survival time. Two of the rats treated with shark cartilage were healthy and fully active at the end of the evaluation period (43 days post implantation). At autopsy the brain tumours of these animals were a factor of approximately 4 smaller than controls. In a repeat study with shark cartilage alone the survival time was extended by approximately 30%. After boronophenylalanine-mediated BNCT, with or without shark cartilage, the survival time of rats that eventually became moribund was increased by a factor of approximately 2 relative to controls. In both treatment groups approximately 20% of rats were healthy at 1 year after BNCT. There was no evidence of residual tumour at post-mortem. It was concluded that shark cartilage, when given alone, significantly increased the survival time of tumour-bearing rats, presumably owing to an anti-angiogenic effect. However, the survival data suggested that boronophenylalanine-mediated BNCT did not appear to be enhanced by the administration of shark cartilage. Publication Types: Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. PMID: 10844870 [PubMed - indexed for MEDLINE] 31: J Cell Biochem. 2000 Jun 6;78(3):417-28. Shark cartilage extract interferes with cell adhesion and induces reorganization of focal adhesions in cultured endothelial cells. Chen JS, Chang CM, Wu JC, Wang SM. Department of Anatomy, College of Medicine, National Taiwan University, Taipei. In this study, we examined the effects of shark cartilage extract on the attachment and spreading properties and the focal adhesion structure of cultured bovine pulmonary artery endothelial cells. Treatment with cartilage extract resulted in cell detachment from the substratum. Immunofluorescence staining of those treated cells that remained attached showed that, instead of being present in both central and peripheral focal adhesions as in control cells, both integrin alpha(v)beta(3) and vinculin were found only in peripheral focal adhesion and thinner actin filament bundles were seen. In addition to causing cell detachment, cartilage extract partially inhibited the initial adherence of the cells to the substratum in a dose-dependent manner. Integrin alpha(v)beta(3) and vinculin staining of these cells also showed a peripheral focal adhesion distribution pattern. Vitronectin induced cell spreading in the absence of serum, but was blocked by simultaneous incubation with cartilage extract, which was shown to inhibit both integrin alpha(v)beta(3) and vinculin recruitment to focal adhesion and the formation of stress fibers. Dot binding assays showed that these inhibitory effects on cell attachment and spreading were not due to direct binding of cartilage extract components to integrin alpha(v)beta(3) or vitronectin. Shark cartilage chondroitin sulfate had no inhibitory effect on either cell attachment or spreading of endothelial cells. These results show that the inhibitory effects of cartilage extract on cell attachment and spreading are mediated by modification of the organization of focal adhesion proteins. Copyright 2000 Wiley-Liss, Inc. Publication Types: Research Support, Non-U.S. Gov't PMID: 10861840 [PubMed - indexed for MEDLINE] 32: Arch Fam Med. 2000 Aug;9(8):692-9. Health food store recommendations for breast cancer patients. Gotay CC, Dumitriu D. Cancer Research Center of Hawaii, Honolulu 96813, USA. cgotay@crch.hawaii.edu CONTEXT: Despite cancer patients' widespread and growing use of complementary and alternative medicine, minimal attention has been paid to the role of health food stores in the "supply side" of this phenomenon. OBJECTIVE: To gain a better understanding of health food store personnel's recommendations for breast cancer patient care. DESIGN: Researcher posing as the daughter of a breast cancer patient and surveying health food store personnel on their product recommendations for cancer care. SETTING: Oahu, Hawaii, summer 1998. PARTICIPANTS: All health food stores (N = 40) offering products for cancer patients. MAIN OUTCOME MEASURES: Recommended products and services, proposed mechanism of action, and costs. RESULTS: Store personnel readily provided information and product recommendations, with shark cartilage being the most frequent. Suggested mechanisms of action drew on traditional healing, scientific, and pseudoscientific rationales. Costs for recommended dosages varied multifold across stores and brands. CONCLUSIONS: Retailers supplying supplements can play an important role in the network of "authorities" for patients with breast and other cancers, as they readily provide advice and recommend products. The reasons why patients seek health food store remedies are useful in developing approaches to patient education. Physicians and other providers are in a key position to assist cancer patients in making informed choices when considering health store products. Publication Types: Review PMID: 10927705 [PubMed - indexed for MEDLINE] 33: Adv Exp Med Biol. 2000;476:209-23. The characterization of angiogenesis inhibitor from shark cartilage. Liang JH, Wong KP. School of Natural Sciences, California State University, Fresno 93740, USA. An angiogenesis inhibitor isolated from shark cartilage, SCF2, has been characterized. SCF2 was shown to have specific angiogenesis-inhibiting activity in endothelial cell culture assays. Results of structural and functional studies indicate that the inhibitor is not a typical protein. It is a heat-stable proteoglycan, which contains keratan sulfate units and peptide. Gel filtration chromatography shows that the molecular weight of the angiogenesis inhibitor is about 10 kd. PMID: 10949667 [PubMed - indexed for MEDLINE] 34: MMW Fortschr Med. 2000 Aug 24;142(33-34):42. [No magic treatment for cancer. Complementary medicine methods, 4: Shark cartilage] [Article in German] Ernst E. Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, UK. PMID: 10998903 [PubMed - indexed for MEDLINE] 35: Proc AMIA Symp. 2000;:794-8. The impact of displayed awards on the credibility and retention of Web site information. Shon J, Marshall J, Musen MA. Stanford Medical Informatics, Stanford University School of Medicine, Stanford, CA 94305-5479, USA. Ratings systems and awards for medical Web sites have proliferated, but the validity and utility of the systems has not been well established. This study examined the effect of awards on the perceived credibility and retention of health information on a Web page. We recruited study participants from Internet newsgroups and presented them with information on the claimed health benefits of shark cartilage. Participants were randomized to receive health information with and without a medical award present on the page. We subsequently asked them to evaluate the credibility of the Web page and posed multiple-choice questions regarding the content of the pages. 137 completed responses were included for analysis. Our results show that the presentation of awards has no significant effect on the credibility or retention of health information on a Web page. Significantly, the highly educated participants in our study found inaccurate and misleading information on shark cartilage to be slightly believable. Publication Types: Clinical Trial Randomized Controlled Trial Research Support, U.S. Gov't, P.H.S. PMID: 11079993 [PubMed - indexed for MEDLINE] 36: Cancer Metastasis Rev. 2000;19(1-2):83-6. Shark cartilage extracts as antiangiogenic agents: smart drinks or bitter pills? Gingras D, Renaud A, Mousseau N, Béliveau R. Laboratoire de médecine moléculaire H pital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Montreal, Quebec, Canada. The use of crude cartilage for the treatment of human cancers remains a subject of controversy. In this brief commentary, we reviewed the current knowledge on the anticancer properties of cartilage. We then presented the properties of AE-941, a novel standardized water-soluble extract derived from shark cartilage that represents less than 5% of the crude cartilage. It is a multifunctional antiangiogenic product that contains several biologically active molecules. EA-941 is one of the few antiangiogenic drugs that is under phase III clinical investigation. It is currently evaluated in Europe and North America for the treatment of refractory renal cell carcinoma and in North America for metastatic non small cell lung cancer. Publication Types: Review PMID: 11191068 [PubMed - indexed for MEDLINE] 37: Biol Pharm Bull. 2001 Feb;24(2):151-4. Demonstration of inhibitory effect of oral shark cartilage on basic fibroblast growth factor-induced angiogenesis in the rabbit cornea. González RP, Soares FS, Farias RF, Pessoa C, Leyva A, de Barros Viana GS, Moraes MO. Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil. raimundo_g@hotmail.com Several angiogenic inhibitors have been obtained from shark cartilage, some of these are currently in clinical trials for assessment of safety and therapeutic efficacy in humans. Still, shark cartilage taken orally is commonly used in alternative and complimentary medicine for various ailments including serious diseases such as cancer. However, only few studies of oral shark cartilage have demonstrated pharmacological effects in experimental animals or patients, to indicate safe doses with sufficient bioavailability. In the present study we demonstrated the antiangiogenic properties of oral shark cartilage in the rabbit cornea model. Slow-release, polymethylmetacrylate pellets containing basic fibroblast growth factor (bFGF) were surgically implanted in the rabbit cornea to stimulate neovascularization scored by stereo microscopy. Powdered shark cartilage (PSC; commercial product) was tested orally along with a water-soluble fraction (WSF) of this cartilage product which was tested by local application. Animals were treated with oral dosages of 100 mg/kg PSC or 200 mg/kg thalidomide as positive control. Pellets containing WSF (50, 100 or 200 microg/pellet) or bFGF-inhibitor pentosan polysulfate were implanted adjacent to the bFGF pellet. Oral shark cartilage inhibited bFGF-induced angiogenesis, as did oral thalidomide, in this in vivo model. WSF and pentosan polysulfate was shown to block neovascularization in the cornea when applied locally. This study demonstrates that in the rabbit, oral shark cartilage appears to produce systemic levels of angiogenesis inhibitors that can exert their effect at the cornea. Publication Types: Research Support, Non-U.S. Gov't PMID: 11217082 [PubMed - indexed for MEDLINE] 38: Med J Aust. 2001 Jan 15;174(2):88-92. Comment in: Med J Aust. 2001 Jun 4;174(11):611-2. Med J Aust. 2001 Sep 17;175(6):342-3. A primer of complementary and alternative medicine commonly used by cancer patients. Ernst E. School of Postgraduate Medicine and Health Sciences, University of Exeter, UK. E.Ernst@exeter.ac.uk Complementary and alternative medicine (CAM) is frequently used by cancer patients, and many oncologists have limited knowledge of CAM. This article provides a brief, evidence-based introduction to several CAM treatments relevant in the context of cancer. "Alternative" diets, chiropractic, coffee enemas, ozone therapy, and shark cartilage seem to have little to offer cancer patients. The evidence for or against homoeopathy and spiritual healing is at present inconclusive. Acupuncture, aromatherapy, and meditation may be useful for nausea/vomiting, for mild relaxation, and for pain/anxiety, respectively. Herbal treatments offer no reasonable prospect of a cure (mistletoe), but could be useful as palliative treatments (eg, for depression [St John's wort] or anxiety [kava]). Our knowledge regarding the potential benefit and harm of CAM is insufficient. Publication Types: Review PMID: 11245510 [PubMed - indexed for MEDLINE] 39: Anticancer Res. 2001 Jan-Feb;21(1A):145-55. Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound. Gingras D, Renaud A, Mousseau N, Beaulieu E, Kachra Z, Béliveau R. Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, 3175, Chemin Côte-Ste-Catherine, Montréal, Québec, Canada H3T 1C5. BACKGROUND: Matrix metalloproteinases (MMPs) play an important role in tissue remodeling under normal physiological and pathological conditions and are thus attractive targets for both diagnostic and therapeutic purposes. Here, we examined the effect of AE-941, an orally bioavailable standardized extract made of cartilage that shows significant antiangiogenic and antimetastatic properties in vivo, on the activity of various members of the MMP family. MATERIALS AND METHODS: The effect of AE-941 on the activity of MMPs was assessed by fluorimetric assays and by substrate gel zymography. RESULTS: AE-941 markedly inhibits the gelatinolytic activity of MMP-2 and to a lesser extent those of MMP-1, MMP-7, MMP-9 and MMP-13. AE-941 also inhibited the elastinolytic activities of MMP-2 and MMP-9 as well as MMP-12 (metalloelastase), porcine pancreatic elastase (PPE), and human leukocyte elastase (HLE). Western blot analysis revealed the presence within AE-941 of immunoreactive TIMP-like proteins, suggesting that these proteins may be at least partly responsible for the observed MMP inhibition. CONCLUSIONS: Taken together, these results demonstrate that AE-941 contains TIMP-like proteins that could be responsible for the specific inhibition of MMPs. Given the recent studies suggesting the presence within this compound of specific inhibitor(s) of endothelial cell proliferation, AE-941 appears as a pleotropic agent able to interfere with several biochemical steps leading to angiogenesis and to other physiopathological conditions. Since AE-941 is currently under Phase III clinical investigations, these findings are also of considerable importance for our understanding of its anticancer properties. Publication Types: Research Support, Non-U.S. Gov't PMID: 11299728 [PubMed - indexed for MEDLINE] 40: Biochim Biophys Acta. 2001 Jan 26;1517(2):311-5. Cloning and characterization of tissue inhibitor of metalloproteinase-3 (TIMP-3) from shark, Scyliorhinus torazame. Kim JT, Kim MS, Bae MK, Song HS, Ahn MY, Kim YJ, Lee SJ, Kim KW. Department of Molecular Biology, Pusan National University, Pusan 609-735, South Korea. We cloned the full-length cDNA encoding TIMP-3 from the cartilage of cloudy dogfish, Scyliorhinus torazame. The entire open reading frame was composed of 645 nucleotides and 214 residues including 12 conserved cysteines and asparagine-184, a putative site for N-linked sugars. It showed about 72% identity to those of other species based on the deduced amino acid sequence. The mRNA of shark TIMP-3 were expressed abundantly in brain and cartilage tissues. To investigate the roles of shark TIMP-3, an expression vector was constructed and transfected into HT1080 human fibrosarcoma cells. Overexpression of shark TIMP-3 reduced the activity of MMP-2 in gelatin zymography. Through human Alu PCR based CAM assay, we also confirmed that shark TIMP-3 transfected HT1080 cells had less intravasation effects. Publication Types: Comparative Study Research Support, Non-U.S. Gov't PMID: 11342115 [PubMed - indexed for MEDLINE] 41: Anticancer Res. 2001 Mar-Apr;21(2A):1065-9. Oral shark cartilage does not abolish carcinogenesis but delays tumor progression in a murine model. Barber R, Delahunt B, Grebe SK, Davis PF, Thornton A, Slim GC. Department of Pathology and Molecular Medicine, Wellington School of Medicine, P.O. Box 7343, Wellington South, New Zealand. BACKGROUND: Shark cartilage and shark cartilage extracts have been reported to have anti-angiogenic and anti-neoplastic properties. This study reports the effects of oral administration of powdered shark cartilage on tumor progression in a murine renal tumor model. MATERIALS AND METHODS: Renal tumors were induced in CBA female mice by a single bolus of IV streptozotocin. 57 mice were fed shark cartilage and the numbers and rate of development of dysplastic convoluted tubules, papillary and solid renal epithelial tumors was compared with 57 control mice over an 88 week follow-up period. RESULTS: In the shark cartilage fed group dysplasia was first observed after 23 weeks (control 19 weeks), papillary tumors after 24 weeks (control 23 weeks) and solid tumors after 55 weeks (control 19 weeks). There was no significant difference in the rate of development of dysplastic tubules between test and control animals. The development of papillary and solid tumors was significantly delayed in the test group. CONCLUSIONS: In this tumor model oral shark cartilage delays, but does not abolish, tumor progression. PMID: 11396141 [PubMed - indexed for MEDLINE] 42: Aust Fam Physician. 2001 Jun;30(6):575-80. Herbal medicine in oncology. Pinn G. Nambour General Hospital, Queensland. Over the years cancer has been more complicated by 'wonder cures' than perhaps any other condition. Remedies such as laetril, shark cartilage, high dose vitamins and many alternative medical practices have been used with little evidence of improvement and sometimes worsened outcome. It is disconcerting that attempts to scientifically discredit these treatments sometimes result in the development of conspiracy theories. However, some plants do contain anticancer agents, the vinca alkaloids (derived from the Madagascar periwinkle) and paclitaxel (derived from the pacific yew tree) are examples of success stories. Extensive screening of tens of thousands of plants has unfortunately revealed only a handful of potential cancer cures. An evidence based approach to alternative treatment in malignancy is appropriate and this seventh article in this series reviews the evidence. PMID: 11458587 [PubMed - indexed for MEDLINE] 43: Arch Dermatol. 2001 Sep;137(9):1149-52. Treatment of Kaposi sarcoma with oral administration of shark cartilage in a human herpesvirus 8-seropositive, human immunodeficiency virus-seronegative homosexual man. Hillman JD, Peng AT, Gilliam AC, Remick SC. Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University, 11100 Euclid Ave, BHC-6, Cleveland, OH 44106, USA. Publication Types: Case Reports Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. PMID: 11559209 [PubMed - indexed for MEDLINE] 44: Biol Pharm Bull. 2001 Oct;24(10):1097-101. Shark cartilage as source of antiangiogenic compounds: from basic to clinical research. González RP, Leyva A, Moraes MO. Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil. raimundo_g@hotmail.com The discovery that angiogenesis is a key condition for the growth of a tumor beyond a millimeter or two, brings about a new approach in the treatment of tumors using drugs able to inhibit the formation of new blood vessels. Also, it has been realized that antiangiogenic drugs can be useful in the treatment of other pathological processes, now classified as angiogenesis-dependent diseases. Initially, cartilage was considered as a possible natural source of antiangiogenic compounds due to its known avascular nature. To date, a number of in vitro and in vivo studies have suggested the existence of antiangiogenic and antitumor compounds in bovine and shark cartilage. However, the potential usefulness of shark cartilage in the treatment of cancer and other angiogenesis-dependent diseases have not been totally accepted due to (i) unsatisfactory patient outcome in clinical trials that have used shark cartilage in cancer patients, (ii) the lack of data that correlates bioavailability with pharmacological effects using oral shark cartilage. Thus, the objective of this review is to describe the main basic and clinical investigations reported in the literature, in which the antiangiogenic and/or antitumor properties of shark cartilage or of its extracts were evaluated. Possible explanations for conflicting results are discussed as well. Publication Types: Review PMID: 11642310 [PubMed - indexed for MEDLINE] 45: J Nutr. 2001 Nov;131(11 Suppl):3037S-40S. Biopharmacologic and herbal therapies for cancer: research update from NCCAM. Richardson MA. National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health, Bethesda, MD, USA. marich@mail.nih.gov During the past decade, use of complementary and alternative medicine (CAM) by the American public increased from 34% in 1990 to 42% in 1995 with related out-of-pocket expenditures estimated at $27 billion. Among cancer patients, use of CAM ranges between 30 and 75% worldwide and includes dietary approaches, herbals and other biologically based treatments such as melatonin, mushrooms, shark cartilage and high dose vitamins and minerals. Concerns about herb-nutrient-drug interactions and product quality and standardization emphasize the need for rigorous research. In 1998, Congress mandated the creation of the National Center for Complementary and Alternative Medicine (NCCAM) to conduct and support such research of CAM therapies. The NCCAM portfolio for oncology is rapidly growing. As of July 2001, 26 projects are underway, two specialized centers are funded for cancer research and four botanical centers are cofunded with the Office of Dietary Supplements. Investigations are targeting herbals and complex herbal formulas; single dietary supplements and complex dietary regimens; biological agents; and mind-body, body-based and frontier approaches. Of these, biopharmacologic and herbal therapies are a major focus of research. The NCCAM portfolio illustrates how research of CAM, particularly studies of biopharmacologic and herbal approaches for cancer, is developing systematically and rigorously. Publication Types: Review PMID: 11694644 [PubMed - indexed for MEDLINE] 46: Oncology (Williston Park). 2001 Oct;15(10):1267-72; discussion 1272-8, 1283. Prevalence of complementary and alternative medicine use in cancer patients. Bernstein BJ, Grasso T. Department of Pharmacy Practice, Nova Southeastern University, College of Pharmacy, Fort Lauderdale, Florida 33328, USA. bberns@nova.edu Interest in complementary and alternative medicine (CAM) has grown dramatically over the past several years. Cancer patients are always looking for new hope, and many have turned to nontraditional means. This study was conducted to determine the prevalence of complementary and alternative medicine use in cancer patients and what if any agents are being used. Approximately, 100 adult cancer patients in a private nonprofit South Florida hospital completed a descriptive cross-sectional survey questionnaire. The mean age of participants was 59 years; 42 patients were male and 58, female. According to survey results, 80% of patients reported using some type of CAM; 81% took vitamins, 54% took herbal products, 30% used relaxation techniques, 20% received massages, and 10% used home remedies. Among patients who took vitamins, 65% said they took a multivitamin, 39% took vitamin C, and 31%, vitamin E. The most common herbal remedies used were green tea, echinacea, shark cartilage, grape seed extract, and milk thistle. Meditation and deep breathing were the two most common relaxation techniques practiced. A large majority of cancer patients are using CAM. In light of the growing interest in CAM, health-care professionals need to be educated about the most common therapies used. Publication Types: Comparative Study PMID: 11702957 [PubMed - indexed for MEDLINE] 47: J Natl Cancer Inst. 2001 Nov 21;93(22):1685. Natural compounds show antiangiogenic activity. Marwick C. Publication Types: News PMID: 11717328 [PubMed - indexed for MEDLINE] 48: Semin Oncol. 2001 Dec;28(6):620-5. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Falardeau P, Champagne P, Poyet P, Hariton C, Dupont E. Aeterna Laboratories Inc., 1405 boulevard du Parc-Technologique, Quebec City, Quebec G1P 4P5, Canada. Recent studies have indicated that bone marrow angiogenesis is increased in multiple myeloma, suggesting that treatment with an antiangiogenic agent might be useful. Among the new antiangiogenic drugs in development, Neovastat (AE-941; Aeterna Laboratories, Quebec City, Canada) can be classified as a naturally occurring multifunctional antiangiogenic agent. It has a marked inhibitory effect on the formation of blood vessels in the chicken embryo vascularization assay (EVT) and endothelial cell proliferation. Furthermore, in vivo experiments showed that oral administration of Neovastat blocks the formation of blood vessels in Matrigel implants containing basic fibroblast growth factor (bFGF). The antiangiogenic activity of Neovastat was found to be associated with two mechanisms of action. In addition to the inhibition of the matrix metalloproteinase activities (MMP-2, MMP-9, and MMP-12), Neovastat inhibits vascular endothelial growth factor (VEGF) binding to endothelial cells, VEGF-dependent tyrosine phosphorylation, and VEGF-induced vascular permeability in mice. Neovastat was also found to have a significant antitumor activity. Oral administration of Neovastat in mice with subcutaneous grafted breast cancer (DA3) cells showed a significant reduction in tumor volume. Neovastat also decreased the number of lung metastases in the Lewis lung carcinoma model. Interestingly, the effect of Neovastat was additive to cisplatin in this model. Furthermore, no treatment-related mortality or loss of body weight was observed. Also, toxicology studies in rats and monkeys demonstrate no dose-limiting toxicity or target organ damage after 1 year of chronic exposure, thus suggesting that Neovastat could be safely administered in humans. Four clinical studies have been conducted to establish the dosing, safety, and early efficacy of Neovastat administered orally. In the oncology field, 482 patients have received Neovastat, of which 146 with solid tumors were exposed to the drug for more than 6 months. Two phase III clinical trials are currently underway. A phase III double-blind placebo-controlled study is being conducted to evaluate the efficacy of Neovastat in addition to induction chemotherapy/radiotherapy combined modality treatment in patients with unresectable non-small cell lung cancer stage IIIA and IIIB. A second phase III randomized, double-blind placebo-controlled study evaluates the efficacy of Neovastat as a monotherapy in metastatic renal cell carcinoma patients who have progressed following a first-line immunotherapy. Neovastat efficacy is also being evaluated in a registration phase II trial in patients with early relapse or refractory multiple myeloma. Copyright 2001 by W.B. Saunders Company. Publication Types: Review PMID: 11740820 [PubMed - indexed for MEDLINE] 49: Lung Cancer. 2001 Dec;34 Suppl 3:S81-9. Angiogenesis inhibitors in the treatment of lung cancer. Shepherd FA. Division of Medical Oncology, Department of Medicine, Princess Margaret Hospital, 610 University Avenue, 5-104, University of Toronto, Ont., Toronto, Canada, M5G 2M9. frances.shepard@uhn.on.ca Numerous inhibitors of angiogenesis are currently under study in lung cancer. Four trials of adjuvant interferon after chemotherapy for small cell lung cancer (SCLC) were negative. Several metalloproteinase inhibitors (MMPIs) are now in study in SCLC and non-small cell lung cancer (NSCLC). Two large randomized trials have closed recently in which Marimastat 10 mg bid was compared to placebo in responding patients with SCLC. Two randomized studies of Prinomastat versus placebo with combination chemotherapy in advanced NSCLC have also completed accrual. The results of these trials are not yet available, but should be reported in mid-2001. A Phase III trial of BMS-275291, a broad-spectrum MMPI in combination with paclitaxel and carboplatin is open for patients with advanced NSCLC. Neovastat, a standardized shark cartilage extract is under study in inoperable Stage III NSCLC. VEG-F gene expression is increased in many tumors including NSCLC, and may act as a paracrine mediator of growth. A randomized Phase II trial of paclitaxel and carboplatin with or without a recombinant humanized anti-VEG-F has been undertaken in NSCLC. Modestly better response and survival were seen with anti-VEG-F and a large Phase III trial is planned. Numerous receptor tyrosine kinases (TK) have been found to be directly or indirectly involved in angiogenesis including Flk-1, Flt-l, Tie-1 and Tie-2. SU5416 is a small molecular TK inhibitor and potent inhibitor of VEG-F-mediated Flk-1 receptor signaling. Another TK inhibitor SU6668 blocks VEG-F, bFGF and PDGF receptor signaling. It is orally available, and it may be evaluated in lung cancer trials in the near future. ZD4190 is an inhibitor of KDR/Flk-1 that may be evaluated in SCLC. Thalidomide has recently been shown in pre-clinical models to be anti-angiogenic. A randomized trial of paclitaxel/carboplatin and radiation with or without thalidomide is open for patients with Stage IIIB NSCLC in the United States. Numerous other anti-angiogenesis agents are in early clinical trials, but have not been evaluated in lung cancer yet. Publication Types: Review PMID: 11740999 [PubMed - indexed for MEDLINE] 50: TreatmentUpdate. 2001 Oct;13(6):6-7. Can low-dose shark cartilage make Kaposi's sarcoma disappear? [No authors listed] Publication Types: Case Reports Comparative Study Newspaper Article PMID: 11768870 [PubMed - indexed for MEDLINE] 51: Semin Urol Oncol. 2001 Nov;19(4):232-46. Results and lessons from clinical trials using dietary supplements for cancer: direct and indirect investigations. Moyad MA. Department of Surgery, University of Michigan Medical Center, Ann Arbor 48109-0330, USA. Randomized controlled trials are generally regarded as the standard of study designs to determine potential causality. The inclusion of a placebo group in these trials, when appropriate, is generally needed to access the efficacy of a drug or dietary supplement. The recent increasing use of dietary supplements and herbal medications by patients makes it imperative to reevaluate the past findings of clinical studies. Several large-scale trials of dietary supplements have been tested in various populations to determine their effect on cancer prevention. Other trials have focused on patients already diagnosed with cancer. In the latter case, it is difficult to involve a placebo because of the serious nature of the disease. Nevertheless, much has been gleaned from these trials directly and indirectly. Overall, when analyzing primary endpoints in these trials, the results have been discouraging and even support the nonuse of certain supplements because of potential adverse effects. Other secondary endpoints in these same trials have revealed some potential encouraging and discouraging data. Individuals who currently qualify for the potential use of dietary supplements for cancer may be restricted to those who have a deficiency in a certain compound despite adequate dietary sources or lifestyle changes. Those individuals with a smoking history or other unhealthy lifestyle seem to have the most to gain or lose from taking certain dietary supplements for cancer. The time seems more than ripe to evaluate past adequate trials with supplements, such as beta-carotene, N-acetyl-cysteine, selenium, shark cartilage, vitamin C, vitamin E, and others. Again, these studies have been disappointing, but they provide insight for the clinician and patient of what to potentially expect when using these supplements for cancer. In addition, indirect trials for other conditions (cardiovascular) may provide future insight into possible results for future cancer prevention trials. Publication Types: Review PMID: 11769876 [PubMed - indexed for MEDLINE] 52: Int J Oncol. 2002 Feb;20(2):299-303. The effect of Neovastat (AE-941) on an experimental metastatic bone tumor model. Weber MH, Lee J, Orr FW. Department of Pathology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada. michael.weber@nrc.ca Bone metastases are generally associated with bone destruction which occurs in response to factors secreted by metastatic cells. Some of these factors secreted by the metastatic cells activate osteoclats while others are proteases that degrade bone collagen. To determine if Neovastat (AE-941), a naturally occurring multi-functional inhibitor of angiogenesis, is able to regulate properties that are thought to have relevance to their propensity to form bone metastases in vivo, we used the human breast cancer MDA-MB-231 cell line which can metastasize to bone. We showed that Neovastat prevented the degradation of osteoid-like radiolabeled extracellular matrices which was induced by incubation of human SaOS-2 osteoblast-like cells with MDA-MB-231 cells. Moreover, Neovastat was demonstrated to inhibit the gelatinolytic activity of matrix metalloproteinase (MMP)-9 expressed by MDA-MB-231 cells. The potential of Neovastat to retard the spread, growth, and osteolysis of MDA-MB-231 cells was then estimated in vivo. Histomorphometric analysis of the vertebral bodies indicated that MDA-MB-231 cells inoculated in nude mice (intracardiac) successfully generate osteolytic metastases with an 83% reduction of the volume of medullary bone (p< or =0.01). However, when tumor-bearing animals were treated orally with Neovastat, there was only a 19% decrease in medullary bone thus indicating that Neovastat can prevent bone metastasis in this model. Consistent with histological results, radiographic analysis indicated that Neovastat decreased the number of osteolytic lesions by 33% (p< or =0.3). Moreover, a decrease in the tumor volume in bone was observed in Neovastat-treated animals. These results indicate that Neovastat may be useful in preventing bone metastasis in cancer patients. Publication Types: Research Support, Non-U.S. Gov't PMID: 11788892 [PubMed - indexed for MEDLINE] 53: Clin Cancer Res. 2002 Apr;8(4):1242-50. The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects. Béliveau R, Gingras D, Kruger EA, Lamy S, Sirois P, Simard B, Sirois MG, Tranqui L, Baffert F, Beaulieu E, Dimitriadou V, Pépin MC, Courjal F, Ricard I, Poyet P, Falardeau P, Figg WD, Dupont E. Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-UQAM, Centre de Cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, Montréal, Québec, H3T 1C5 Canada. PURPOSE: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, which exerts direct effects on vascular endothelial cells, including endothelial cell proliferation and survival, tubulogenesis, and vascular permeability. In this study, we examined whether Neovastat, a naturally occurring multifunctional antiangiogenic drug, could inhibit the endothelial cell response to VEGF stimulation. RESULTS: We demonstrated that Neovastat was able to block the VEGF-dependent microvessel sprouting from Matrigel-embedded rat aortic rings, and it also blocked the VEGF-induced endothelial cell tubulogenesis in vitro. In vivo studies showed that Neovastat was able to specifically inhibit VEGF-induced plasma extravasation in numerous tissues, including pancreas and skin. The mechanism of action of Neovastat on VEGF-mediated effects was also evaluated at the molecular level. Neovastat was shown to compete against the binding of VEGF to its receptor in endothelial cells and significantly inhibited the VEGF-dependent tyrosine phosphorylation of VEGF receptor-2, whereas it had no significant effect on VEGF receptor-1 activity. Moreover, the inhibition of receptor phosphorylation was correlated with a marked decrease in the ability of VEGF to induce pERK activation. Neovastat does not compete against the binding of basic fibroblast growth factor, indicating a preferential inhibitory effect on the VEGF receptor. CONCLUSIONS: Because Neovastat was shown previously to inhibit metalloproteinase activities, these results suggest that Neovastat is able to target multiple steps in tumor neovascularization, further emphasizing its use as a pleiotropic, multifunctional antiangiogenic drug. Publication Types: In Vitro Research Support, Non-U.S. Gov't PMID: 11948139 [PubMed - indexed for MEDLINE] 54: Clin Exp Metastasis. 2002;19(2):145-53. Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Dupont E, Falardeau P, Mousa SA, Dimitriadou V, Pepin MC, Wang T, Alaoui-Jamali MA. Les Laboratoires AEterna Inc, Québec, Canada. A novel naturally occurring antiangiogenic agent isolated from cartilage, referred to as Neovastat (AE-941), was examined for its efficacy against tumor neovascularization and progression. Exposure to Neovastat results in ex ovo antiangiogenic properties in the chorioallantoid membrane of chicken embryo (71% decrease in the angiogenic index as compared to the basic fibroblast growth factor (bFGF) treated control embryos, P < 0.0001). Oral administration of Neovastat inhibits bFGF-induced angiogenesis in the Matrigel mouse model (87.5% decrease in hemoglobin as compared to the bFGF-treated control implants, P < 0.0001). Neovastat also induces a dose response decrease of lung metastases in the Lewis lung carcinoma model (oral administration; 69.1% of inhibition obtained at the maximal dose of 0.5 ml/day, P < 0.0001). Combined with a sub-optimal dose of cisplatinum (2 mg/kg, i.p.), Neovastat (0.5 ml/day) improved the therapeutic index by increasing the antimetastatic efficacy and by exerting a protective activity against cisplatinum-induced body weight loss and myelosuppression. In summary, our experimental data provide evidence of antiangiogenic and antimetastatic properties of Neovastat, following oral administration. PMID: 11964078 [PubMed - indexed for MEDLINE] 55: Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2001;33(1):99-104. SCAIF80, a Novel Inhibitor of Angiogenesis, and Its Effect on Tumor Growth. Shen XR, Ji DM, Hu YQ, Jia FX, Wang L, Chu ZY, Ren DM. State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai 200433, China. xianrong.sh@yahoo.com A novel inhibitor of angiogenesis named SCAIF80 (shark cartilage-derived angiogenesis inhibitory factor) from shark cartilage has been isolated and characterized. SDS-PAGE analysis followed by silver staining revealed a single band with molecular weight (M(r)) of 80 kD. To determine whether this protein was capable of inhibiting angiogensis, it was assayed in endothelial cell (EC) proliferation and migration assay. The results showed that SCAIF80 significantly suppressed EC proliferation and migration in a dose-dependent manner. In the chick chorioallantoic membrane (CAM) assay, SCAIF80 also showed a potent inhibitory activity on angiogenesis in vivo. In animal tests, the growth of tumor was potently suppressed by SCAIF80 therapy. Lewis lung carcinoma was inhibited by 93.83 % at a dose of 5 mg/(kg.d). These findings suggest that shark cartilage may produce a novel protein with anti-angiogenic and anti-tumor activity. PMID: 12053197 [PubMed - as supplied by publisher] 56: Clin Exp Pharmacol Physiol. 2002 Aug;29(8):731-4. Problems in the use of herbal and natural substances, with a specific example concerning the cardiovascular system. Pang PK, Benishin C, Lewanczuk R, Shan J. International Research and Development Program on Traditional Chinese and Natural Medicine, The University of Hong Kong, Hong Kong SAR, China. peter@cvtechnologies.com 1. There has been increasing awareness and use of natural preparations for health purposes by consumers. 2. However, recent studies have repeatedly shown that many natural products marketed as nutraceuticals or health food do not deliver the health benefit as claimed and are inconsistent from batch to batch. 3. The present paper describes the scientific rationale of such inconsistency and uses an antihypertensive preparation as an example to demonstrate the significant value of natural products if developed scientifically and properly. Publication Types: Review PMID: 12100011 [PubMed - indexed for MEDLINE] 57: Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2000;32(1):43-48. Purification and Functional Characterization of a Shark Cartilage Factor Inhibitory to Angiogenesis. Shen XR, Ji DM, Jia FX, Deng XX, Sun JH, Hu XR, Ren DM. Naval Medical Research Institute, Shanghai 200433, China. 970240@fudan.edu.cn SCAIF-I, an inhibitor of angiogenesis from shark cartilage was purified to homogeneity. The 4 mol/L guanidinium chloride extract of shark cartilage was fractionally precipitated with 35%-65% acetone, then purified by Resource Q ion exchange chromatography, Sephacryl S-300 gel filtration, and reverse-phase high performance liquid chromatography. The pure inhibitor was homogeneous as a single band on a silver-stained 15% sodium dodecyl sulfate-polyacrylamide gel. SCAIF-I had an molecular weight of 18 kD. It specifically inhibited proliferation of endothelial cells, and strongly blocked endothelial cell movement and angiogenesis in the chorioallantoic membrane of chick embryos. Systemic administration of SCAIF-I at the dose of 5 mg/kg.d suppressed 87.93% of the growth of Lewis lung carcinoma implanted in C57BL/6 mice. PMID: 12110912 [PubMed - as supplied by publisher] 58: Am J Ind Med. 2002 Jul;42(1):50-4. Fatal asthma from powdering shark cartilage and review of fatal occupational asthma literature. Ortega HG, Kreiss K, Schill DP, Weissman DN. National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, HELD/ASB/Mailstop L-4218, 1095 Willowdale Rd., Morgantown, West Virginia 26505, USA. BACKGROUND: Work-related asthma (WRA) is the most common work-associated respiratory disease in developed countries. METHOD: We report shark cartilage dust as a new potential cause of occupational asthma (OA) in the context of other fatal OA case reports. RESULTS: A 38-year-old white male worked for 8 years in a facility which primarily granulated and powdered various plastics. Sixteen months prior to his death, the plant began grinding shark cartilage. After 10 months of exposure, he reported chest symptoms at work in association with exposure to shark cartilage dust and a physician diagnosed asthma. Six months later, he complained of shortness of breath at work and died from autopsy-confirmed asthma. The latency from onset of exposure to symptoms and from symptom onset to death was shorter than 10 previously reported OA fatalities. CONCLUSION: Recognition of occupational causes and triggers of asthma and removal of affected individuals from these exposures is critical and can prevent progression to irreversible or even fatal asthma. Copyright 2002 Wiley-Liss, Inc. Publication Types: Case Reports Review PMID: 12111690 [PubMed - indexed for MEDLINE] 59: Expert Rev Anticancer Ther. 2001 Oct;1(3):341-7. AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. Gingras D, Batist G, Béliveau R. Laboratiore de médicine moléculaire Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, 3175, Chemin Côte-Ste-Catherine, Montréal, Québec H3T 1C5, Canada. AE-941 (Neovastat) is a naturally occurring product extracted from cartilage and has antiangiogenic properties. It has reached Phase III clinical trial evaluation for the treatment of solid tumors (non-small cell lung cancer and renal cell carcinoma) and a pivotal Phase II clinical trial in multiple myeloma is ongoing. AE-941 inhibits several steps of the angiogenesis process, including matrix metalloproteinase activities and VEGF signaling pathways. Moreover, AE-941 induces endothelial cell apoptosis and tissue-type plasminogen activator activity, thus suggesting that it is a multifunctional antiangiogenic drug. Results from Phase I/II clinical trials indicate that AE-941, given orally, is well tolerated. Moreover, the median survival time in patients with renal cell carcinoma and non-small cell lung cancer was significantly longer in patients receiving high doses of AE-941 compared to low doses. PMID: 12113101 [PubMed - indexed for MEDLINE] 60: Expert Rev Anticancer Ther. 2001 Jun;1(1):3-4. AEterna reports on its phase II trial of neovastat. [No authors listed] Publication Types: Clinical Trial Clinical Trial, Phase II News PMID: 12113128 [PubMed - indexed for MEDLINE] 61: Blood Rev. 2002 Sep;16(3):167-74. Novel therapies for multiple myeloma. Ryoo JJ, Cole CE, Anderson KC. Harvard Medical School, MA, USA. Multiple myeloma (MM) continues to evade cure by conventional therapies, increasing the urgency for new, biologically based treatments. Reviewed in this discussion are novel chemotherapies under clinical trial that capitalize upon greater comprehension of tumor pathophysiology. In targeting tumor biology, these therapies serve as a model of treatment with great potential for improving outcomes in patients with MM. Publication Types: Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Review PMID: 12163002 [PubMed - indexed for MEDLINE] 62: Ann Oncol. 2002 Aug;13(8):1259-63. Neovastat (AE-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels. Batist G, Patenaude F, Champagne P, Croteau D, Levinton C, Hariton C, Escudier B, Dupont E. McGill Center for Translational Research in Cancer, McGill University, Montréal, Quebec, Canada. gbatist@onc.jgh.mcgill.ca BACKGROUND: renal cell carcinoma (RCC) is a potential target for anti-angiogenic drugs because of its high vascularization. Neovastat (AE-941) is an inhibitor of angiogenesis with a mechanism of action that could prove beneficial in the treatment of RCC. Patients and design A phase II trial was conducted to identify the long-term safety profile of Neovastat in advanced cancer patients and to obtain preliminary information on its efficacy in solid tumors refractory to standard treatments. Neovastat (60 or 240 ml/day) was administered orally (b.i.d.) to 144 patients with solid tumors refractory to standard therapies or for whom no standard treatments were available. RESULTS: A survival analysis was conducted on 22 patients with a primary diagnosis of refractory RCC to determine whether the dose of Neovastat had any effect. A significant relationship between dose and survival was observed; the median survival time was significantly longer (16.3 versus 7.1 months; P = 0.01) in patients treated with Neovastat 240 ml/day (n = 14) compared with patients receiving 60 ml/day (n = 8). No dose-limiting toxicity was reported. The most frequent adverse event was taste alteration (13.6%). CONCLUSIONS: Neovastat is well tolerated by advanced cancer patients at doses of 60 and 240 ml/day. The higher dose of Neovastat administered in this trial is associated with a survival benefit in RCC, which is not explained by differences in major prognostic factors. Publication Types: Clinical Trial Clinical Trial, Phase II Comparative Study Multicenter Study Research Support, Non-U.S. Gov't PMID: 12181250 [PubMed - indexed for MEDLINE] 63: J Am Acad Dermatol. 2002 Oct;47(4):535-41. Neovastat (AE-941), an inhibitor of angiogenesis: Randomized phase I/II clinical trial results in patients with plaque psoriasis. Sauder DN, Dekoven J, Champagne P, Croteau D, Dupont E. Department of Dermatology, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287, USA. There is considerable evidence to support an immunopathogenic basis of psoriasis. However, changes such as altered angiogenesis have also been implicated in the pathogenesis of psoriasis. AE-941 (Neovastat; Aeterna Laboratories, Quebec City Quebec, Canada) is a naturally occurring product currently in clinical investigation that blocks two main mechanisms of angiogenesis activation, namely, vascular endothelial growth factor and matrix metalloproteinase. We hypothesized that psoriasis could be modulated by inhibiting the neovascularization of psoriatic plaques. We conducted a randomized dose-comparison trial to evaluate the safety and potential therapeutic benefit of AE-941, administered orally to patients with psoriasis. Forty-nine patients with psoriasis were enrolled and assigned to receive AE-941 at 30, 60, 120, or 240 mL/d for 12 weeks. Patients were followed up for another 12-week period. Improvement in the Psoriasis Area and Severity Index (PASI) score was observed in 50%, 41.7%, and 30.8% of the patients receiving 240, 120, and 60 mL/d, respectively. No patients receiving a dosage 30 mL/d showed a PASI score improvement. A statistically significant improvement with increasing dose was observed for the PASI score, severity of itch, and the physician's global assessment. The most commonly reported nonserious drug-related adverse events affected the gastrointestinal system in 12 of 49 patients (primarily nausea, diarrhea, vomiting, flatulence, and constipation) and the skin and appendages in 4 of 49 patients (primarily acne and rash). This randomized phase I/II study provides evidence that the antiangiogenic agent AE-941 offers a new therapeutic approach to the management of psoriasis. Publication Types: Clinical Trial Clinical Trial, Phase I Clinical Trial, Phase II Randomized Controlled Trial Research Support, Non-U.S. Gov't PMID: 12271297 [PubMed - indexed for MEDLINE] 64: Prog Urol. 2002 Sep;12(4):703-8. [Metastatic kidney cancer: new therapeutic approaches] [Article in French] Negrier S, Mejean A, Oudard S, Escudier B. Département d'Oncologie Médicale, Centre Léon Bérard, 28, rue Laënnec, 69373 Lyon, France. negrier@lyon.fnclcc.fr Several promising approaches to the treatment of renal cancer have been developed over recent years. Two independent North American and European studies have demonstrated the value of nephrectomy in patients with metastatic disease: the overall survival of patients treated with interferon was improved by nephrectomy, essentially in patients with a good general status. Several publications have also emphasized the value of surgery for metastases. New experimental approaches have also been developed. Dendritic cells fused with tumour cells induced 4 complete remissions and 2 partial remissions in a series of 17 patients. Allogeneic haematopoietic stem cell transplantation induced lasting remissions in 10 out of 17 patients. The National Cancer Institute team, in the United States, has developed this approach for patients with an HLA-compatible relative. Finally, various molecules with promising antiangiogenic properties are currently under development in renal cancer. Publication Types: English Abstract Review PMID: 12463140 [PubMed - indexed for MEDLINE] 65: Mol Cancer Ther. 2002 Aug;1(10):795-802. The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis. Boivin D, Gendron S, Beaulieu E, Gingras D, Béliveau R. Laboratoire de médecine moléculaire, Hôpital Ste-Justine-Université du Quebec à Montréal, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, Montreal, Quebec H3T 1C5, Canada. Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent, has been shown to inhibit key components of the angiogenic process, including matrix metalloproteinases and vascular endothelial growth factor-mediated signaling events. In this study, we report the presence of a proapoptotic activity within this compound. Neovastat treatment of bovine aortic endothelial cells caused cell death with characteristics of apoptosis, including chromatin condensation and DNA fragmentation. Neovastat markedly induced caspase-3, caspase-8, and caspase-9 activities, at similar levels to those measured in cells treated with tumor necrosis factor-alpha. Activation of caspases by Neovastat appears to be essential for its proapoptotic effects because all apoptotic features were blocked by zVAD-fmk, a broad-spectrum caspase inhibitor. The activation of caspases was correlated with the cleavage of the nuclear substrate poly(ADP-ribose) polymerase, and by a concomitant release of cytochrome c from mitochondria to the cytoplasm. Neovastat-induced apoptosis appears to be specific to endothelial cells because treatment of other cell types such as U-87, COS-7, NIH-3T3, and SW1353 did not result in increased caspase-3 activity. These results demonstrate that Neovastat contains a proapoptotic factor that specifically induces the activation of caspases in endothelial cells and the resulting apoptosis of these cells. Publication Types: Research Support, Non-U.S. Gov't PMID: 12492112 [PubMed - indexed for MEDLINE] 66: Expert Rev Anticancer Ther. 2002 Dec;2(6):618. FDA grants orphan-drug status to Aeterna's Neovastat for kidney cancer. [No authors listed] Publication Types: News PMID: 12503200 [PubMed - indexed for MEDLINE] 67: Anticancer Drugs. 2003 Feb;14(2):91-6. Neovastat--a novel antiangiogenic drug for cancer therapy. Gingras D, Boivin D, Deckers C, Gendron S, Barthomeuf C, Béliveau R. Laboratoire de médecine moléculaire Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, Montréal, Québec, Canada. Neovastat (AE-941) is an antiangiogenic drug isolated from marine cartilage. It interferes with several steps associated with the development of angiogenesis through its ability to induce endothelial cell apoptosis, and to inhibit matrix metalloproteinase activities and vascular endothelial growth factor-mediated signaling pathways, suggesting that Neovastat behaves as a multifunctional antiangiogenic drug. Neovastat is orally bioavailable, and shows significant antitumor and antimetastatic properties in animal models. An excellent safety profile with few side effects has been monitored in more than 800 patients who have been exposed to Neovastat, some of whom for more than 4 years. This indicates that Neovastat is suitable for long-term use, either alone or in combination with other anticancer therapies. Accordingly, Neovastat is currently under evaluation in three pivotal clinical studies with two phase III clinical trials in patients with lung and renal carcinoma, and a phase II clinical trial in patients with multiple myeloma is ongoing. Copyright 2003 Lippincott Williams & Wilkins Publication Types: Review PMID: 12569294 [PubMed - indexed for MEDLINE] 68: J Cutan Med Surg. 2003 May-Jun;7(3):208-16. Modulation of the contact hypersensitivity response by AE-941 (Neovastat), a novel antiangiogenic agent. Dupont E, Wang B, Mamelak AJ, Howell BG, Shivji G, Zhuang L, Dimitriadou V, Falardeau P, Sauder DN. AEterna Laboratories, Quebec, Quebec, Canada. BACKGROUND: AE-941 (Neovastat) is an angiogenesis inhibitor noted to have antiinflammatory properties. OBJECTIVE: We tested Neovastat in a contact hypersensitivity (CHS) model to determine the mechanism of action of its antiinflammatory effects. METHODS: Neovastat was orally administered (200 mg/kg/day) during the sensitization and challenge phases of a murine CHS assay and inflammatory responses were measured. Subsequent assays were performed on mice treated with Neovastat or Cortisone (120 mg/kg/day, IP) and differential mRNA expression of several pro- and antiinflammatory cytokines was quantified using RT-PCR. RESULTS: Neovastat decreased inflammation by 39% when administered during sensitization but did not alter the CHS response when given during the challenge phase. Neovastat significantly induced IL-10 expression in skin and skin-draining lymph nodes (49% and 45%, respectively) and decreased IFNgamma expression in the lymph nodes (35%). CONCLUSION: Antiinflammatory effects of Neovastat observed in CHS could be linked to modulation of cytokines early in the sensitization phase. Publication Types: Research Support, Non-U.S. Gov't PMID: 12574904 [PubMed - indexed for MEDLINE] 69: Support Care Cancer. 2003 Apr;11(4):197-8. Epub 2003 Mar 12. Comment on: Support Care Cancer. 2003 Apr;11(4):232-5. Dangerous nutrition. Jungi WF. Publication Types: Comment Editorial Review PMID: 12673456 [PubMed - indexed for MEDLINE] 70: Support Care Cancer. 2003 Apr;11(4):232-5. Epub 2003 Jan 15. Comment in: Support Care Cancer. 2003 Apr;11(4):197-8. Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer-related hypercalcemia. Lagman R, Walsh D. Department of Medical Oncology, Cleveland Clinic Cancer Center, Cleveland Clinic Foundation, 9500 Euclid Avenue M76, Cleveland, OH 44195, USA. The use of nutritional supplements in the general population and in cancer patients has become very popular. These supplements are not perceived as medications and are presumed to be safe by cancer patients, who may however be at risk for hypercalcemia. We note that many of our patients who have developed symptomatic hypercalcemia were taking vitamin D, calcium, or shark cartilage supplements. We report eight cases of hypercalcemia in cancer patients seen at the Cleveland Clinic Foundation in whom these nutritional supplements may have contributed to the prevalence or severity of hypercalcemia. Publication Types: Case Reports PMID: 12673461 [PubMed - indexed for MEDLINE] 71: Int Immunopharmacol. 2003 May;3(5):657-69. Immunomodulating principles from shark cartilage. Part 1. Isolation and biological assessment in vitro. Kralovec JA, Guan Y, Metera K, Carr RI. Bioscience Enterprise Centre, Ocean Nutrition Canada Ltd., 1721 Lower Water Street, Halifax, Nova Scotia, Canada B3J 1S5. jkralovec@ocean-nutrition.com Extracts from shark cartilage exhibiting powerful immunostimulating activity in vitro are described. The study shows that a simple extraction with water is very effective in producing the immunostimulating principles and implies that it is ideal for scale-up and manufacturing on a large scale. The extracts are potent stimulators of B cells and macrophages isolated from BALB/c mice spleen while stimulation of T cells was insignificant in our in vitro models. The study demonstrates that the active principles are thermally stable proteoglycans with molecular masses exceeding 100 kDa. This in vitro study represents an important step needed for further assessment of the products in vivo and their value for nutraceutical use. Publication Types: In Vitro Research Support, Non-U.S. Gov't PMID: 12757735 [PubMed - indexed for MEDLINE] 72: Osteoarthritis Cartilage. 2003 Jun;11(6):433-41. Oral absorption and bioavailability of ichthyic origin chondroitin sulfate in healthy male volunteers. Volpi N. Department of Biologia Animale, Biological Chemistry Section, University of Modena and Reggio Emilia, Modena, Italy. volpi@unimo.it OBJECTIVE: Chondroitin sulfate (CS) has proven to be a valuable therapeutic tool as a symptomatic slow-acting drug for the treatment of osteoarthritis after oral administration. The aim of this study was to assess the absorption of CS of ichthyic origin after oral administration to 20 healthy male volunteers. DESIGN: Ichthyic origin CS (from shark cartilage, 4 g) was orally administered to 20 healthy human volunteers, and then extracted and purified from plasma over a 48 h period. The polysaccharide absorbed by oral route was characterized and quantified by agarose-gel electrophoretic technique, and densitometric scanning. In addition, the percentage of constituent disaccharides and charge density were measured. RESULTS: After oral administration, ichthyic CS plasma levels increased (more than 120%) with a peak concentration at 8.7h, with the increase reaching significance from 4 to 16 h. A significant decrease in the relative amount of non-sulfated disaccharide was measured (reaching the minimum relative percentage of 30.86+/-20.79% at 8h). At the same time, 4-sulfated disaccharide increased to a maximum of 51.91+/-25.91% at 6h, and 6-sulfated and disulfated disaccharides appeared in blood, reaching maximum concentrations of 15.24+/-16.60% at 8h and 2.93+/-4.82% at 12h, respectively. Concomitantly, the mean charge density rose from 0.40+/-0.14 at predose to a maximum of 0.72+/-0.22 and 0.72+/-0.21 measured 8 and 12h after ichthyic CS administration. CONCLUSIONS: Ichthyic CS is absorbed slowly, with a t(max)=8.7+/-4.5h and the C(max)averaged 4.87+/-2.05 microg/ml. The differences in the absorption and bioavailability of the various CS formulations is strongly influenced by the structure and characteristics, such as molecular mass, charge density, and cluster of disulfated disaccharides, of the parental molecules. PMID: 12801483 [PubMed - indexed for MEDLINE] 73: Int Immunopharmacol. 2003 Jul;3(7):921-6. Modulation of CD(4)(+) and CD(8)(+) tumor infiltrating lymphocytes by a fraction isolated from shark cartilage: shark cartilage modulates anti-tumor immunity. Feyzi R, Hassan ZM, Mostafaie A. Department of Immunology, School of Medical Sciences, Tarbiat Modares University, P O Box 14115-111, Tehran, Iran. Shark cartilage has proven to have some inhibitory effects on angiogenesis, metastasis, cell adhesion and proteolysis. In this study, we wanted to study some of the effects of shark cartilage on tumor immune response. Firstly, by means of chromatographic methods and delayed type hypersensitivity (DTH) test, we optimized a procedure for isolation and purification of a shark cartilage protein fraction with most immunostimulatory effects. Then, we examined its effect on the infiltration of CD(4)(+) and CD(8)(+) lymphocytes into a murine tumor model. Our fraction was composed of two major proteins with molecular weights (MWs) of about 14 and 15 kDa. This fraction highly increases DTH response against sRBC in mice. Furthermore, intraperitoneal injection of this fraction to tumor-bearing mice could increase T-cell infiltration into the tumor. Also, there was a significant increase in the CD(4)/CD(8) ratio in tumor infiltrating lymphocytes, but no such changes were found in the peripheral blood lymphocytes. According to these results, we suppose that this fraction is a good candidate for further studies in cancer therapy. Also, we concluded that this fraction, with previously proven anti-angiogenic effects, can augment cellular immune response and T-cell infiltration into the tumor and thus, there may be a direct relationship between angiogenesis inhibition and T-cell infiltration. PMID: 12810349 [PubMed - indexed for MEDLINE] 74: Br Poult Sci. 2003 May;44(2):218-23. The effect of supplementing layer diets with shark cartilage or chitosan on egg components and yolk lipids. Nogueira CM, Zapata JF, Fuentes MF, Freitas ER, Craveiro AA, Aguiar CM. Departamento de Tecnologia de Alimentos, Universidade Federal do Ceará, Fortaleza, CE, Brasil. 1. An experiment was designed to evaluate the effects of the addition of shark cartilage (SC) or chitosan (CH) to layer diets on egg component weights, yolk lipids and hen plasma lipids. 2. Hy-Line laying hens (80) were used during a 56 d feeding trial. Treatments were: basal diet (BD), BD + 20 g/kg SC, BD + 30 g/kg SC, BD + 20 g/kg CH and BD + 30 g/kg CH. Eggs were analysed on d 14, 28, 42 and 56. 3. Egg weight and egg component weights were not affected by these treatments throughout the experimental period. 4. After 14d of experimental feeding, cholesterol levels were higher in eggs from birds given BD + 20 g/kg CH and BD + 30 g/kg CH than in those from birds given BD. 5. Furthermore, eggs from hens given BD + 20 g/kg SC or BD + 20 g/kg CH were higher in palmitic and stearic acids and lower in oleic acid than those from birds fed on BD. After 56 d feeding, however, palmitic and stearic acid contents in eggs from hens given any of the supplemented diets were lower than in those from hens given BD, and oleic acid in eggs from hens given BD + 20 g/kg SC, BD + 30 g/kg SC and BD + 30 g/kg CH was higher than in those from birds fed on BD. 6. Plasma cholesterol and triacylglycerol levels were not significantly affected by dietary treatment. 7. Shark cartilage or chitosan at up to 30 g/kg in layer diets did not affect egg component weights (yolk, white and shell) and total lipid contents. During the period from 42 to 56d of experimental feeding, diets containing up to 30 g/kg chitosan reduced egg yolk contents of cholesterol, palmitic and stearic acids and increased the content of oleic acid. Publication Types: Research Support, Non-U.S. Gov't PMID: 12828207 [PubMed - indexed for MEDLINE] 75: Expert Opin Investig Drugs. 2003 Aug;12(8):1403-11. AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Bukowski RM. Experimental Therapeutics Program, The Cleveland Clinic Taussig Cancer Center, Cleveland, OH 44195, USA. bukowsr@cc.ccf.org The therapy of renal cell carcinoma remains a challenge for medical oncologists and urologists. During the past 10 years, the molecular abnormalities occurring in various subtypes of renal cancer, such as clear cell renal carcinoma, have been well described. The genetic abnormalities found in clear cell tumours involve chromosome 3p and, additionally, hypermethylation of the von Hippel-Lindau (VHL) gene can be detected. The VHL protein is involved in the angiogenic cascade in non-hypoxic conditions, and the possible role of mutant or hypermethylated VHL protein in promoting angiogenesis is, therefore, of interest. The majority of patients with renal cell carcinoma who receive treatment, such as IL-2 and/or IFN, fail and develop progressive disease. Therapy is therefore inadequate and novel approaches, such as those inhibiting angiogenesis, are of interest. The agent AE-941 (Neovostat trade mark; AEterna) was developed based on the observation that shark cartilage may contain biologically active inhibitors of angiogenesis. A variety of in vitro and in vivo activities of this preparation have been identified. At the molecular level, AE-941 appears to exhibit four different potential mechanisms of action: modulation of matrix proteases; inhibition of vascular endothelial growth factor binding to its receptor; induction of endothelial cell apoptosis; and stimulation of angiostatin production. The antitumour effects of AE-941 are seen in multiple murine models and involve not only effects on primary tumour growth but also on development of metastases. AE-941 is administered orally and has an excellent toxicity profile. Of interest are the findings in patients with renal cell carcinoma. Preliminary trials in this setting have suggested that responses to AE-941 occur and that patients receiving higher doses of this agent may have improved survival. Based on these preliminary data, a large, multi-institutional, randomised, Phase III trial of this agent has now been conducted in patients with metastatic clear cell carcinoma of the kidney. Over 300 patients have been entered into this trial, accrual is complete and results still remain preliminary. The clinical studies in a malignancy such as renal cell carcinoma will provide sentinel and potentially important observations on the clinical effectiveness of this agent. Publication Types: Review PMID: 12882625 [PubMed - indexed for MEDLINE] 76: Semin Oncol Nurs. 2003 Aug;19(3):180-92. Anti-angiogenesis in cancer therapy. Muehlbauer PM. Clinical Center Nursing Department, National Institutes of Health, Bethesda, MD, USA. OBJECTIVE: To review tumor angiogenesis, identify potential targets for anti-angiogenic cancer therapy, and highlight certain anti-angiogenic agents in clinical trials. DATA SOURCE: Research articles, abstracts, review articles, and book chapters. CONCLUSION: Tumor angiogenesis is a complex, multistep process that provides a target for antineoplastic therapy whereby tumor neovasculature is interrupted at various steps in the angiogenic process. Clinical trials are investigating the application and efficacy of anti-angiogenic agents. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses must continually increase their knowledge with the onset of newer, targeted agents. This will provide a background for educating and caring for the patient who is receiving anti-angiogenic therapy. Publication Types: Review PMID: 12962008 [PubMed - indexed for MEDLINE] 77: Cancer Biother Radiopharm. 2003 Aug;18(4):497-511. Recent developments and future directions in the treatment of multiple myeloma. Pichardo D, Singhal S, Mehta J, Rosen S. Division of Hematology-Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center and Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, USA. d-pichardo@md.northwestern.edu Multiple Myeloma (MM) is a B cell neoplasia affecting approximately 14,400 new individuals in the United States each year. Although MM remains an incurable disease, encouraging advances have been made in its therapy in the recent past. High dose chemotherapy with autologous stem cell transplantation has been shown in randomized controlled trials to improve survival in MM and is currently considered the first line treatment for all patients except those with advanced age of co-morbidities. For such patients, conventional chemotherapy with melphalan and steroids continue to be the treatment of choice. The use of tandem stem cell transplants and the use of both myeloablative and nonmyeloablative allogeneic stem cell transplantation remains investigational. Thalidomide is a new therapeutic option with promising results; however, it is associated with significant side effects including deep venous thrombosis and peripheral neuropathy. Its use in combination with other chemotherapy agents is still under investigation. Novel promising agents are currently under clinical trials including Proteosome Inhibitors and much more potent thalidomide analogs or immunomodulators. This review summarizes recent developments in the therapy and supportive care of MM and introduces the newer drugs in preclinical and early clinical trials. Publication Types: Review PMID: 14503944 [PubMed - indexed for MEDLINE] 78: J Gastrointest Surg. 2003 Dec;7(8):961-8; discussion 969. Troponin I peptide (Glu94-Leu123), a cartilage-derived angiogenesis inhibitor: in vitro and in vivo effects on human endothelial cells and on pancreatic cancer. Kern BE, Balcom JH, Antoniu BA, Warshaw AL, Fernández-del Castillo C. Department of Surgery,Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. Several inhibitors of angiogenesis have been identified in bovine and shark cartilage. One of them is troponin I, which is the molecule responsible for the inhibition of the actomyosin ATPase during muscle contraction. In this study we sought to investigate if the active site of troponin I (peptide Glu94-Leu123; pTnI) is also the one responsible for the antiangiogenic properties of this protein. The effects of pTnI on endothelial cell tube formation and endothelial cell division were investigated using human umbilical vein endothelial cells, Matrigel, light microscopy, carboxyfluorescein diacetate, succinimidyl esterlabeling, and flow cytometry. Its effects on induction of ICAM-1 and production of vascular endothelial growth factor by pancreatic cancer cells (CAPAN-1) were also investigated, as was its efficacy in a mouse model of pancreatic cancer metastases. Our results show that concentrations as low as 1 pg/ml of pTnI significantly inhibit endothelial cell tube formation, and that endothelial cell division was inhibited at 96 hours by 3 microg/ml pTnI (P=0.0001). No effects were seen using troponin peptide 124-181 as a control. pTnI-treated supernatant from the pancreatic cancer cell line CAPAN-1 downregulated ICAM-1 expression on human umbilical vein endothelial cells up to 10 ng/ml pTnI, and a significant reduction in vascular endothelial growth factor production was seen by treating CAPAN-1 cells with up to 1 microg/ml pTnI. After intrasplenic injection of CAPAN-1 cells, mice treated with pTnI had fewer liver metastases compared to control mice (liver/body weight 5.5 vs. 11.1; P=0.03). The active region of troponin I is the one responsible for its antiangiogenic effect. The mechanism of action of this peptide is probably multifactorial. PMID: 14675705 [PubMed - indexed for MEDLINE] 79: Invest New Drugs. 2004 Jan;22(1):17-26. The antiangiogenic agent Neovastat (AE-941) stimulates tissue plasminogen activator activity. Gingras D, Labelle D, Nyalendo C, Boivin D, Demeule M, Barthomeuf C, Béliveau R. Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, 3175, Chemin Côte-Ste-Catherine, Montréal, Québec, (Canada) H3T 1C5. The plasminogen activator/plasmin system represents a key component of the proteolytic machinery underlying angiogenesis. In this work, we investigated the effect of Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent that is currently in Phase III clinical trials, on tissue and urokinase plasminogen activator activities. We found that in vitro, Neovastat at 100 microg/ml markedly stimulates t-PA-mediated plasmin generation, while it slightly inhibits the generation of plasmin mediated by uPA. The stimulatory effect of Neovastat on t-PA activity was markedly increased by a heat treatment, resulting in a 15-fold increase in the rate of activation of plasminogen. Neovastat did not directly stimulate the activity of t-PA or plasmin towards exogenous substrates, suggesting that its effect requires the presence of plasminogen. Accordingly, kinetic analysis showed that Neovastat increases both the k(cat) of t-PA as well as its affinity for plasminogen by 10-fold. The stimulation of t-PA activity by Neovastat was also correlated with a direct interaction of Neovastat with plasminogen as monitored by the surface plasmon resonance technology. Overall, these results identify Neovastat as a potent stimulator of t-PA-dependent activation of plasminogen, further emphasizing its pleiotropic mechanism of action on several molecular events involved in angiogenesis. Publication Types: Research Support, Non-U.S. Gov't PMID: 14707491 [PubMed - indexed for MEDLINE] 80: Mar Biotechnol (NY). 2002 Dec;4(6):521-5. Sharks: a potential source of antiangiogenic factors and tumor treatments. Cho J, Kim Y. Department of Microbiology, Pukyong National University, Pusan 608-737, Korea. Since angiogenesis is a key feature of tumor growth, inhibiting this process is one way to treat cancer. Cartilage is a natural source of material with strong antiangiogenic activity. This report reviews knowledge of the anticancer properties of shark cartilage and clinical information on drugs such as neovastat and squalamine. Because their entire endoskeleton is composed of cartilage, sharks are thought to be an ideal source of angiogenic and tumor growth inhibitors. Shark cartilage extract has shown antiangiogenic and antitumor activities in animals and humans. The oral administration of cartilage extract was efficacious in reducing angiogenesis. Purified antiangiogenic factors from shark cartilage, such as U-995 and neovastat (AE-941), also showed antiangiogenic and antitumor activity. AE-941 is under phase III clinical investigation. Squalamine, a low molecular weight aminosterol, showed strong antitumor activity when combined with chemotherapeutic materials. The angiogenic tissue inhibitor of metalloprotease 3 (TIMP-3) and tumor suppressor protein (snm23) genes from shark cartilage were cloned and characterized. PMID: 14961226 [PubMed] 81: Vet Clin North Am Small Anim Pract. 2004 Jan;34(1):249-69, viii. The use of nutraceuticals in cancer therapy. Roudebush P, Davenport DJ, Novotny BJ. Technical Information Services, Hill's Pet Nutrition, Inc. Hill's Science and Technology Center, PO Box 1658, Topeka, KS 66601, USA. phil_roudebush@hillspet.com The high prevalence of nutraceutical use among human patients with cancer suggests that the use of nutraceuticals in pet animals with cancer is probably common. Dogs with a wide variety of malignant diseases have significant alterations in carbohydrate, protein, and fat metabolism. These metabolic alterations may be ameliorated by using functional foods relatively low in soluble carbohydrate, moderate amounts of protein that includes sources of arginine, and moderate amounts of fat supplemented with omega-3 long-chain polyunsaturated fatty acids. Well-controlled clinical studies in a variety of species with cancer, including rodents, people, and dogs, have documented that increased dietary and serum levels of omega-3 fatty acids are associated with a number of health benefits, including improved disease-free interval, survival time, and quality of life. Other nutraceuticals of interest in patients with cancer include antioxidant vitamins, trace minerals, glutamine, protease inhibitors, garlic, tea polyphenols, vitamin A, and shark cartilage. Publication Types: Review PMID: 15032131 [PubMed - indexed for MEDLINE] 82: Biochem Biophys Res Commun. 2004 Jul 16;320(1):205-12. Activation of tissue plasminogen activator gene transcription by Neovastat, a multifunctional antiangiogenic agent. Gingras D, Nyalendo C, Di Tomasso G, Annabi B, Béliveau R. Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, 3175, Chemin Côte-Ste-Catherine, Montréal, Que., Canada H3T 1C5. We recently reported that Neovastat, an antiangiogenic drug that is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer, may inhibit angiogenesis through an increase in tPA activity. Here, we show that Neovastat also stimulates tPA gene transcription in endothelial cells, in a TNFalpha-like manner. RT-PCR analysis and gene reporter assays using the human tPA promoter indicated that upregulation of the tPA gene transcription by both Neovastat and TNFalpha was correlated with the phosphorylation of JNK1/2 and of IkappaB and that SP600125 and BAY11-7082, inhibitors of JNK and IkappaK, respectively, inhibit the increase of tPA gene transcription induced by Neovastat and TNFalpha. These results suggest that Neovastat induces tPA gene transcription through activation of the JNK and NFkappaB signaling pathways, leading to an increase of tPA secretion by endothelial cells. This may lead to the localized destruction of the fibrin provisional matrix that is necessary for neovessel formation and thus contribute to the reported antiangiogenic properties of this compound. Publication Types: Research Support, Non-U.S. Gov't PMID: 15207722 [PubMed - indexed for MEDLINE] 83: MMW Fortschr Med. 2004 Apr 22;146(17):8, 10. Comment in: MMW Fortschr Med. 2004 May 20;146(21):17. [From shark cartilage to hypnosis. Conservative medicine against cancer?] [Article in German] Arnheim K. Publication Types: Comparative Study News PMID: 15224894 [PubMed - indexed for MEDLINE] 84: Curr Opin Investig Drugs. 2004 Jun;5(6):668-77. AE-941 (AEterna). Dredge K. Centre for Immunology and Cancer Research, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, QLD 4102, Australia. kdredge@cicr.uq.edu.au AEterna is developing AE-941, an angiogenesis inhibitor derived from the ultrafiltration of liquid shark cartilage, with matrix metalloprotease (MMP)-2, MMP-9 and vascular endothelial growth factor inhibitory properties, for the potential treatment of non-small-cell lung cancer. Publication Types: Review PMID: 15242256 [PubMed - indexed for MEDLINE] 85: J Herb Pharmacother. 2002;2(2):71-93. Shark cartilage monograph: a clinical decision support tool. Hammerness P, Ulbricht C, Barrette EP, Boon H, Szapary P, Sollars D, Smith M, Tsourounis C, Bent S, Basch E. Natural Standard Research Collaboration, Cambridge, MA 02138-5204, USA. The use, adverse effects, mechanism of action, pharmacology, interactions and supporting evidence of shark cartilage is presented. Dosage, toxicology and safety parameters are also discussed. PMID: 15277099 [PubMed] 86: Drugs R D. 2004;5(2):83-9. AE 941. [No authors listed] AE 941 [Arthrovas, Neoretna, Psovascar] is shark cartilage extract that inhibits angiogenesis. AE 941 acts by blocking the two main pathways that contribute to the process of angiogenesis, matrix metalloproteases and the vascular endothelial growth factor signalling pathway. When initial development of AE 941 was being conducted, AEterna assigned the various indications different trademarks. Neovastat was used for oncology, Psovascar was used for dermatology, Neoretna was used for ophthalmology and Arthrovas was used for rheumatology. However, it is unclear if these trademarks will be used in the future and AEterna appears to only be using the Neovastat trademark in its current publications regardless of the indication. AEterna Laboratories signed commercialisation agreements with Grupo Ferrer Internacional SA of Spain and Medac GmbH of Germany in February 2001. Under the terms of the agreement, AEterna has granted exclusive commercialisation and distribution rights to AE 941 in oncology to Grupo Ferrer Internacional for the Southern European countries of France, Belgium, Spain, Greece, Portugal and Italy. It also has rights in Central and South America. Medac GmbH will have marketing rights in Germany, the UK, Scandinavia, Switzerland, Austria, Ireland, the Netherlands and Eastern Europe. In October 2002, AEterna Laboratories announced that it had signed an agreement with Australian healthcare products and services company Mayne Group for marketing AE 941 (as Neovastat) in Australia, New Zealand, Canada and Mexico. In March 2003, AEterna Laboratories announced it has signed an agreement with Korean based LG Life Sciences Ltd for marketing AE 941 (as Neovastat) in South Korea. The agreement provides AEterna with upfront and milestone payments, as well as a return on manufacturing and sales of AE 941. AEterna Laboratories had granted Alcon Laboratories an exclusive worldwide licence for AE 941 for ophthalmic products. However, this licence has been terminated. In 1999, AEterna secured funding for AE 941, part of which is from Technology Partnerships Canada (TPC), a research support programme run by Canada's federal government. Industry Canada will contribute $Can 1 for every $Can3 spent by AEterna on the development of AE 941, up to a total figure of $Can29.4 million. AEterna will reimburse TPC upon commercialisation of AE 941-derived products as a royalty on income generated. In January 2004 AEterna announced that development of AE 941 would be focusing on non-small cell lung cancer and that development for renal cell carcinoma would be discontinued. AEterna had previously announced in January 2003, following its acquisition of Zentaris, that development of AE 941 would be "strictly focused" on renal and non-small cell lung cancer, suggesting that development for all other indications has been discontinued, at least for the foreseeable future. Publication Types: Review PMID: 15293867 [PubMed - indexed for MEDLINE] 87: Arch Biochem Biophys. 2004 Nov 15;431(2):197-206. Purification and characterization of a stimulator of plasmin generation from the antiangiogenic agent Neovastat: identification as immunoglobulin kappa light chain. Boivin D, Provençal M, Gendron S, Ratel D, Demeule M, Gingras D, Béliveau R. Laboratoire de médecine moléculaire, Hôpital Sainte-Justine-UQAM, Centre de cancérologie, Charles-Bruneau, Centre de Recherche de l'Hôpital Sainte-Justine, 3175, Chemin Côte-Sainte-Catherine, Montreal, Que., Canada H3T 1C5. We have recently shown that Neovastat, an antiangiogenic extract from shark cartilage, stimulates the in vitro activation of plasminogen by facilitating the tissue-type plasminogen activator (tPA)-dependent conversion of plasminogen to plasmin. In this report, we describe the purification and characterization of the stimulatory molecules. Neovastat was subjected to a three-step purification procedure including gel filtration, preparative isoelectric focusing, and preparative SDS-PAGE. Two 28-kDa proteins with pIs of approximately 4.5 and 6.5 were purified to apparent homogeneity and identified as immunoglobulin (Ig) kappa light chains by N-terminal microsequencing. Ig light chains do not directly stimulate the activity of tPA or plasmin, suggesting a mechanism of action involving an interaction with plasminogen. Kinetic analysis showed that both Ig light chains accelerate the in vitro tPA-dependent conversion of plasminogen in plasmin by increasing the affinity of tPA for plasminogen by 32- and 38-fold (Km decrease from 456 nM to 12-14 nM). Shark Ig light chains also stimulated the degradation of fibrin by the tPA/plasminogen system in an in vitro assay. A direct interaction between Ig light chains and plasminogen (KA=4.0-5.5 x 10(7) M(-1); KD=18-25 nM) and with tPA (KA=2.8 x 10(7) M(-1); KD=36 nM) was demonstrated using real time binding measured by surface plasmon resonance. Ig light chain is the first molecule associated with the antiangiogenic activity of Neovastat to be purified and identified. Publication Types: Research Support, Non-U.S. Gov't PMID: 15488468 [PubMed - indexed for MEDLINE] 88: J Allergy Clin Immunol. 2004 Nov;114(5):1227-8. Occupational asthma caused by shark cartilage dust. San-Juan S, Garcés M, Caballero ML, Monzón S, Moneo I. Publication Types: Case Reports Letter PMID: 15536437 [PubMed - indexed for MEDLINE] 89: Thromb Res. 2005;115(1-2):143-52. Direct-acting fibrinolytic enzymes in shark cartilage extract: potential therapeutic role in vascular disorders. Ratel D, Glazier G, Provençal M, Boivin D, Beaulieu E, Gingras D, Béliveau R. Laboratoire de Médecine Moléculaire Ste-Justine-UQAM, Centre de Cancérologie Charles-Bruneau, Hôpital Ste-Justine et Université du Québec à Montréal, 3175 Chemin Côte-Ste-Catherine, Montréal, QC, Canada H3T 1C5. Fibrinogen and fibrin are molecules with overlapping roles in blood clotting, fibrinolysis, wound healing, inflammation, matrix and cellular interactions and neoplasia. There is currently much interest in the possible use of fibrinolytic agents in human therapeutics. In this study, we report the presence of fibrinolytic activities in shark cartilage extract (SCE). In vitro, SCE at 100 microg/ml completely degraded fibrin gel in an aprotinin-insensitive manner, suggesting a non-plasmin molecular nature. SCE was able to cleave all chains of fibrinogen and fibrin and the cleavage was completely inhibited by 1,10-phenanthroline, suggesting an essential role for metalloprotease(s) in this process. Using fibrinogen zymography, we show that SCE contains two plasmin-independent fibrinolytic activities and that these activities are correlated with the presence of 58 and 62 kDa proteases in the extract. SCE-fibrinolytic activities are inhibited by dithiothreitol, suggesting that disulfide bonds are necessary for the protease structure. Finally, using thromboelastography, SCE markedly induced retraction of human platelet-rich plasma (PRP) clot, this process being completely abolished by 1,10-phenanthroline. These data suggest the presence of novel non-plasmin fibrinolytic activities within SCE. This extract may thus represent a potential source of new therapeutic molecules to prevent and treat vaso-occlusive and thromboembolic disorders. Publication Types: Research Support, Non-U.S. Gov't PMID: 15567466 [PubMed - indexed for MEDLINE] 90: Cancer Res. 2004 Dec 1;64(23):8485-91. Erratum in: Cancer Res. 2005 Jan 1;65(1):374. Shark cartilage, cancer and the growing threat of pseudoscience. Ostrander GK, Cheng KC, Wolf JC, Wolfe MJ. Department of Biology and Department of Comparative Medicine, Johns Hopkins University, Baltimore, Maryland 21218, USA. gofish@jhu.edu The promotion of crude shark cartilage extracts as a cure for cancer has contributed to at least two significant negative outcomes: a dramatic decline in shark populations and a diversion of patients from effective cancer treatments. An alleged lack of cancer in sharks constitutes a key justification for its use. Herein, both malignant and benign neoplasms of sharks and their relatives are described, including previously unreported cases from the Registry of Tumors in Lower Animals, and two sharks with two cancers each. Additional justifications for using shark cartilage are illogical extensions of the finding of antiangiogenic and anti-invasive substances in cartilage. Scientific evidence to date supports neither the efficacy of crude cartilage extracts nor the ability of effective components to reach and eradicate cancer cells. The fact that people think shark cartilage consumption can cure cancer illustrates the serious potential impacts of pseudoscience. Although components of shark cartilage may work as a cancer retardant, crude extracts are ineffective. Efficiencies of technology (e.g., fish harvesting), the power of mass media to reach the lay public, and the susceptibility of the public to pseudoscience amplifies the negative impacts of shark cartilage use. To facilitate the use of reason as the basis of public and private decision-making, the evidence-based mechanisms of evaluation used daily by the scientific community should be added to the training of media and governmental professionals. Increased use of logical, collaborative discussion will be necessary to ensure a sustainable future for man and the biosphere. Publication Types: Research Support, U.S. Gov't, P.H.S. PMID: 15574750 [PubMed - indexed for MEDLINE] 91: Johns Hopkins Med Lett Health After 50. 2004 Oct;17(8):1-2, 7. The new cancer blockers. [No authors listed] PMID: 15602777 [PubMed - indexed for MEDLINE] 92: J Microbiol. 2005 Feb;43(1):11-6. Neovastat (AE-941) inhibits the airway inflammation and hyperresponsiveness in a murine model of asthma. Lee SY, Paik SY, Chung SM. Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Republic of Korea. Matrix metalloproteinase (MMP)-9 plays an important role in the pathogenesis of bronchial asthma. Neovastat, having significant antitumor and antimetastatic properties, is classified as a naturally occurring multifunctional antiangiogenic agent. We evaluated the therapeutic effect of Neovastat on airway inflammation in a mouse model of asthma. BALB/c mice were immunized subcutaneously with ovalbumin (OVA) on days 0, 7, 14, and 21 and challenged with inhaled OVA on days 26, 29, and 31. Neovastat was administrated by gavage (5 mg/kg body weight) three times with 12 h intervals, beginning 30 min before OVA inhalation. On day 32, mice were challenged with inhaled methacholine, and enhanced pause (Penh) was measured as an index of airway hyperresponsiveness. The severity of airway inflammation was determined by differential cell count of bronchoalveolar lavage (BAL) fluid. The MMP-9 concentration in BAL fluid samples was measured by ELISA, and MMP-9 activity was measured by zymography. The untreated asthma group showed an increased inflammatory cell count in BAL fluid and Penh value compared with the normal control group. Mice treated with Neovastat had significantly reduced Penh values and inflammatory cell counts in BAL fluid compared with untreated asthmatic mice. Furthermore, mice treated with Neovastat showed significantly reduced MMP-9 concentrations and activity in BAL fluid. These results demonstrate that Neovastat might have new therapeutic potential for airway asthmatic inflammation. Publication Types: Research Support, Non-U.S. Gov't PMID: 15765051 [PubMed - indexed for MEDLINE] 93: Health News. 2005 Mar;11(3):15. Shark cartilage cancer treatments are pseudoscience. [No authors listed] Publication Types: News PMID: 15818787 [PubMed - indexed for MEDLINE] 94: Int Immunopharmacol. 2005 Jun;5(6):961-70. Low molecular weight fraction of shark cartilage can modulate immune responses and abolish angiogenesis. Hassan ZM, Feyzi R, Sheikhian A, Bargahi A, Mostafaie A, Mansouri K, Shahrokhi S, Ghazanfari T, Shahabi S. Department of Immunology, School of Medical Sciences, Tarbiat Modarres University, P.O. Box: 14115-111, Tehran, IR Iran. hasan_zm@modares.ac.ir Shark cartilage has proven to have inhibitory effects on angiogenesis. In this research, we studied the effects of shark cartilage on the immune system. Firstly, we isolated and purified a shark cartilage protein fraction with the most immunostimulatory effects. Our fraction was composed of two proteins with molecular weights of about 14 and 15 kDa. This fraction highly augments delayed-type hypersensitivity response against sRBC in mice, and decreases the cytotoxic activity of Natural Killer cells. Furthermore, intraperitoneal injection of this fraction to tumor-bearing mice could increase T-cell infiltration into the tumor, and decrease the tumor lesion size. Also, this fraction has strong inhibitory effect on HBMEC proliferation and migration in fibrin matrix. According to these results, we suppose that this fraction is a good candidate for further studies in cancer therapy. PMID: 15829412 [PubMed - indexed for MEDLINE] 95: Cancer. 2005 Jul 1;104(1):176-82. Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Loprinzi CL, Levitt R, Barton DL, Sloan JA, Atherton PJ, Smith DJ, Dakhil SR, Moore DF Jr, Krook JE, Rowland KM Jr, Mazurczak MA, Berg AR, Kim GP; North Central Cancer Treatment Group. Department of Oncology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 56301, USA. cloprinzi@mayo.edu BACKGROUND: Shark cartilage has been a popular complementary or alternative medicine intervention. The basis for this popularity is the claim that sharks rarely get cancer because of the high proportion of cartilage in the shark's body. However, early studies were equivocal. Therefore, a clinical trial was conducted to look at the impact of shark cartilage in patients with advanced cancer. The primary goal of this trial was to determine whether a shark cartilage product improved overall survival for patients with advanced cancer who were getting standard care. Secondary research goals were to evaluate toxicities, tolerability, and quality of life associated with this shark cartilage product. METHODS: The study was a two-arm, randomized, placebo-controlled, double-blind, clinical trial. Patients with incurable breast or colorectal carcinoma had to have good performance status and organ function. Patients could be receiving chemotherapy. Patients were all to receive standard care and then to be randomly selected to receive either a shark cartilage product or an identical-appearing and smelling placebo 3 to 4 times each day. RESULTS: Data on a total of 83 evaluable patients were analyzed. There was no difference in overall survival between patients receiving standard care plus a shark cartilage product versus standard care plus placebo. Likewise, there was no suggestion of improvement in quality of life for patients receiving the shark cartilage, compared with those receiving placebo. CONCLUSION: This trial was unable to demonstrate any suggestion of efficacy for this shark cartilage product in patients with advanced cancer. Publication Types: Clinical Trial Clinical Trial, Phase III Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S. PMID: 15912493 [PubMed - indexed for MEDLINE] 96: J Natl Cancer Inst. 2005 Nov 2;97(21):1562-3. Sharks do get cancer: few surprises in cartilage research. Finkelstein JB. Publication Types: News PMID: 16264172 [PubMed - indexed for MEDLINE] 97: BMJ. 2006 Dec 9;333(7580):1222. Shark cartilage in the water: Ignorance-based cancer treatment. Richmond C. London SW3 5AQ c@roline.demon.co.uk. PMID: 17158402 [PubMed - indexed for MEDLINE] 98: BMJ. 2006 Dec 9;333(7580):1221-2. Shark cartilage in the water: one size does not fit all. Noble SI. Publication Types: Letter PMID: 17158397 [PubMed - indexed for MEDLINE] 99: BMJ. 2006 Dec 9;333(7580):1222. Shark cartilage in the water: Effective legislation is already in place but is not being properly used. Shepherd CB. Stroud, Gloucestershire GL6 8EH charlesbshepherd@lineone.net. PMID: 17158403 [PubMed - indexed for MEDLINE] 100: Int Immunopharmacol. 2007 Mar;7(3):383-91. Epub 2006 Dec 21. Induction of inflammatory cytokines by cartilage extracts. Merly L, Simjee S, Smith SL. Department of Biological Sciences, Florida International University, University Park, Miami, FL 33199, United States. Shark cartilage extracts were examined for induction of cytokines and chemokines in human peripheral blood leukocytes. Primary leukocyte cultures were exposed to a variety of aqueous and organic extracts prepared from several commercial brands of shark cartilage. From all commercial sources of shark cartilage tested the acid extracts induced higher levels of TNFalpha than other extracts. Different commercial brands of shark cartilage varied significantly in cytokine-inducing activity. TNFalpha induction was seen as early as 4 h and IFNgamma at detectable levels for up to four days. Shark cartilage extracts did not induce physiologically significant levels of IL-4. Results suggest that shark cartilage, preferentially, induces Th1 type inflammatory cytokines. When compared to bovine cartilage extract, collagen, and chondroitin sulfate, shark cartilage induced significantly higher levels of TNFalpha. Treatment with digestive proteases (trypsin and chymotrypsin) reduced the cytokine induction response by 80%, suggesting that the active component(s) in cartilage extracts is proteinaceous. The induction of Th1 type cytokine response in leukocytes is a significant finding since shark cartilage, taken as a dietary supplement for a variety of chronic degenerative diseases, would be contraindicated in cases where the underlying pathology of the chronic condition is caused by inflammation. Publication Types: Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PMID: 17276897 [PubMed - indexed for MEDLINE] 101: Cancer Biol Ther. 2007 May;6(5):775-80. Epub 2007 Feb 12. A novel polypeptide from shark cartilage with potent anti-angiogenic activity. Zheng L, Ling P, Wang Z, Niu R, Hu C, Zhang T, Lin X. Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China; Graduate School of the Chinese Academy of Sciences, Beijing, China. Using guanidine-HCl extraction, acetone precipitation, ultra-filtration and chromatography, a novel polypeptide with potent anti-angiogenic activity was purified from cartilage of the shark, Prionace glauca. N-terminal amino acid sequence analysis and SDS-PAGE revealed that the substance is a novel polypeptide with MW 15500 (PG155). The anti-angiogenic effects of PG155 were evaluated using zebrafish embryos model in vivo. Treatment of the embryos with 20 mug/ml PG155 resulted in a significant reduction in the growth of subintestinal vessels (SIVs). A higher dose resulted in almost complete inhibition of SIV growth, as observed by endogenous alkaline phosphatase (EAP) staining assay. An in vitro transwell experiment revealed that the polypeptide inhibited vascular endothelial growth factor (VEGF) induced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs in 20 mug/ml PG155 significantly decreased the density of migrated cells. Almost complete inhibition of cell migration was found when HUVECs were treated with 40-80 mug/ml PG155. PG155 (20 mug/ml) markedly inhibited the tube formation of HUVECs and a dose-dependent effect was also found when treatment of HUVECs with PG155 at the concentration from 20-160 mug/ml. PMID: 17426448 [PubMed - in process] 102: J Urol. 2007 Nov;178(5):1901-5. Epub 2007 Sep 17. Prognostic factors of metastatic renal cell carcinoma after failure of immunotherapy: new paradigm from a large phase III trial with shark cartilage extract AE 941. Escudier B, Choueiri TK, Oudard S, Szczylik C, Négrier S, Ravaud A, Chevreau C, Venner P, Champagne P, Croteau D, Dupont E, Hariton C, Bukowski RM. Institut Gustave Roussy, Villejuif, France. PURPOSE: We analyzed prognostic factors, described survival and generated a prognostic model in patients with metastatic renal cell carcinoma in whom immunotherapy failed and who were potentially eligible for novel agents. MATERIALS AND METHODS: An analysis of the relationship between clinical features and survival was performed in 300 patients with advanced renal cell carcinoma in whom immunotherapy had failed and who were subsequently treated as part of a single, phase III clinical trial with the anti-angiogenic agent Neovastat (shark cartilage extract AE 941). Clinical features were first examined univariately and a stepwise modeling approach based on Cox proportional hazard regression was then performed to generate a multivariate model. RESULTS: Median and progression-free survival (prognostic factors) for the whole cohort was 12.6 and 2 months, respectively. Prognostic features associated with shorter survival on multivariate analysis were the number of metastatic sites (greater than 1), time from nephrectomy to metastatic disease (less than 2 years), high alkaline phosphatase, abnormal corrected serum Ca and high lactate dehydrogenase (greater than 1.5 x the upper limit of normal). Four prognostic subgroups were identified by counting the number of adverse prognostic factors. Median survival in patients with zero adverse prognostic factors was 15.6 months compared to 11.7 months in patients with 1, 8.5 months in patients with 2 and 3.5 months in patients with 3 or more. CONCLUSIONS: We identified 4 risk groups to predict survival in previously treated patients with renal cell carcinoma. This model was based on data from what is to our knowledge the largest experience in this population. It should be used in clinical trial design, risk stratification and patient counseling. Publication Types: Clinical Trial, Phase III Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't PMID: 17868728 [PubMed - indexed for MEDLINE] 103: Med Monatsschr Pharm. 2007 Sep;30(9):351. [Shark cartilage extract. No effect on bronchial carcinoma] [Article in German] [No authors listed] PMID: 17912881 [PubMed - indexed for MEDLINE]