Cartilage (Bovine and Shark) General Information Bovine (cow) cartilage and shark cartilage have been investigated as treatments for cancer, psoriasis, arthritis, and a number of other medical conditions for more than 30 years.[1-9] Reviewed in [10-16] At least some of the interest in cartilage as a treatment for cancer arose from the mistaken belief that sharks, whose skeletons are made primarily of cartilage, are not affected by this disease. Reviewed in [12,17] Although reports of malignant tumors in sharks are rare, a variety of cancers have been detected in these animals. Reviewed in [17-19] Nonetheless, several substances that have antitumor activity have been identified in cartilage.[20-42] Reviewed in [2-4,7,11-16,41,43-45] More than half a dozen clinical studies of cartilage as a treatment for cancer have already been conducted,[2-4,7-9,45] Reviewed in [6,11-15] and additional clinical studies are now under way.[46-49] Reviewed in [6,11] The absence of blood vessels in cartilage led to the hypothesis that cartilage cells (also known as chondrocytes) produce 1 or more substances that inhibit blood vessel formation. Reviewed in [23-26,31,32,44] The formation of new blood vessels, or angiogenesis, is necessary for tumors to grow larger than a few millimeters in diameter (i.e., larger than approximately 100,000 to 1,000,000 cells) because tumors, like normal tissues, must obtain most of their oxygen and nutrients from blood. Reviewed in [29,30,37,50-53] A developing tumor, therefore, cannot continue to grow unless it establishes connections to the circulatory system of its host. It has been reported that tumors can initiate the process of angiogenesis when they contain as few as 100 cells.[52] Inhibition of angiogenesis at this early stage may, in some instances, lead to complete tumor regression.[52] The possibility that cartilage could be a source of 1 or more types of angiogenesis inhibitors for the treatment of cancer has prompted much research. The major structural components of cartilage include several types of the protein collagen and several types of glycosaminoglycans, which are polysaccharides. Reviewed in [16,25,26,35,44,53,54] Chondroitin sulfate is the major glycosaminoglycan in cartilage. Reviewed in [35,53] Although there is no evidence that the collagens in cartilage, or their breakdown products, can inhibit angiogenesis, there is evidence that shark cartilage contains at least 1 angiogenesis inhibitor that has a glycosaminoglycan component (see Laboratory/Animal/Preclinical Studies).[42] Other data indicate that most of the antiangiogenic activity in cartilage is not associated with the major structural components. Reviewed in [22,26,44] Some glycosaminoglycans in cartilage reportedly have anti-inflammatory and immune-system–stimulating properties,[55,56] Reviewed in [1,2,10,12] and it has been suggested that either they or some of their breakdown products are toxic to tumor cells.[20] Reviewed in [2,3] Thus, the antitumor potential of cartilage may involve more than 1 mechanism of action. Cartilage products are sold commercially in the United States as dietary supplements. More than 40 different brand names of shark cartilage alone are available to consumers. Reviewed in [14] In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because manufacturers of cartilage products are not required to show evidence of anticancer or other biologic effects, Reviewed in [14] it is unclear whether any of these products has therapeutic potential. In addition, individual products may vary considerably from lot to lot because standard manufacturing processes do not exist, and binding agents and fillers may be added during production. Reviewed in [14] The FDA has not approved the use of cartilage as a treatment for cancer or any other medical condition. To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the FDA. To date, IND status has been granted to at least 4 groups of investigators to study cartilage as a treatment for cancer.[7,46,47,57] Reviewed in [15] Because the IND application process is confidential and because the existence of an IND can be disclosed only by the applicants, it is not known whether other applications have been made. In animal studies, cartilage products have been administered in a variety of ways. In some studies, oral administration of either liquid or powdered forms has been used.[16,35,36,39,40,58] Reviewed in [11,43] In other studies, cartilage products have been given by injection (intravenous or intraperitoneal), applied topically, or placed in slow-release plastic pellets that were surgically implanted.[22,23,28,29,31,34,36,38,40] Reviewed in [24,42,44] Most of the latter studies investigated the effects of cartilage products on the development of blood vessels in the chorioallantoic membrane of chicken embryos, the cornea of rabbits, or the conjunctiva of mice.[22,23,28,31,34,36,38,40] Reviewed in [24,42,44] In human studies, cartilage products have been administered topically or orally, or they have been given by enema or subcutaneous injection.[2-4,7-9,46-49] Reviewed in [6,11-13,15] For oral administration, liquid, powdered, and pill forms have been used.[2-4,7-9,46-49] Reviewed in [6,11-13,15] The dose and duration of cartilage treatment have varied in human studies, in part because different types of products have been tested. In this summary, the brand name (i.e., registered or trademarked name) of the cartilage product(s) used in individual studies will be identified wherever possible. References Prudden JF, Balassa LL: The biological activity of bovine cartilage preparations. Clinical demonstration of their potent anti-inflammatory capacity with supplementary notes on certain relevant fundamental supportive studies. Semin Arthritis Rheum 3 (4): 287-321, 1974 Summer. [PUBMED Abstract] Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985. [PUBMED Abstract] Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985. [PUBMED Abstract] Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994. Dupont E, Savard PE, Jourdain C, et al.: Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis. J Cutan Med Surg 2 (3): 146-52, 1998. [PUBMED Abstract] Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001. [PUBMED Abstract] Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998. [PUBMED Abstract] Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998. Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-554, 1999. Prudden JF, Migel P, Hanson P, et al.: The discovery of a potent pure chemical wound-healing accelerator. Am J Surg 119 (5): 560-4, 1970. [PUBMED Abstract] AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999. [PUBMED Abstract] Cassileth BR: Shark and bovine cartilage therapies. In: Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. New York, NY: WW Norton & Company, 1998, pp 197-200. Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. Last accessed June 11, 2004. Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1: 414-16, 1995. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995. [PUBMED Abstract] Fontenele JB, Araújo GB, de Alencar JW, et al.: The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent. Biol Pharm Bull 20 (11): 1151-4, 1997. [PUBMED Abstract] Harshbarger JC, Ostrander GK: Cancer in sharks, skates, rays, and other lower fishes. [Abstract] Proc Am Assoc Cancer Res 41: A-4848, 2000. Schlumberger HG, Lucke B: Tumors of fishes, amphibians, and reptiles. Cancer Res 8: 657-754, 1948. Wellings SR: Neoplasia and primitive vertebrate phylogeny: echinoderms, prevertebrates, and fishes--A review. Natl Cancer Inst Monogr 31: 59-128, 1969. [PUBMED Abstract] Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. J Biol Response Mod 4 (6): 590-5, 1985. [PUBMED Abstract] Murray JB, Allison K, Sudhalter J, et al.: Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. J Biol Chem 261 (9): 4154-9, 1986. [PUBMED Abstract] Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990. [PUBMED Abstract] Moses MA, Sudhalter J, Langer R: Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes. J Cell Biol 119 (2): 475-82, 1992. [PUBMED Abstract] Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr. [PUBMED Abstract] Takigawa M, Pan HO, Enomoto M, et al.: A clonal human chondrosarcoma cell line produces an anti-angiogenic antitumor factor. Anticancer Res 10 (2A): 311-5, 1990 Mar-Apr. [PUBMED Abstract] Ohba Y, Goto Y, Kimura Y, et al.: Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochim Biophys Acta 1245 (1): 1-8, 1995. [PUBMED Abstract] Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977. [PUBMED Abstract] Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976. [PUBMED Abstract] Langer R, Conn H, Vacanti J, et al.: Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc Natl Acad Sci U S A 77 (7): 4331-5, 1980. [PUBMED Abstract] Takigawa M, Shirai E, Enomoto M, et al.: Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation of endothelial cells in culture. Cell Biol Int Rep 9 (7): 619-25, 1985. [PUBMED Abstract] Takigawa M, Shirai E, Enomoto M, et al.: A factor in conditioned medium of rabbit costal chondrocytes inhibits the proliferation of cultured endothelial cells and angiogenesis induced by B16 melanoma: its relation with cartilage-derived anti-tumor factor (CATF). Biochem Int 14 (2): 357-63, 1987. [PUBMED Abstract] Hiraki Y, Inoue H, Iyama K, et al.: Identification of chondromodulin I as a novel endothelial cell growth inhibitor. Purification and its localization in the avascular zone of epiphyseal cartilage. J Biol Chem 272 (51): 32419-26, 1997. [PUBMED Abstract] Pauli BU, Memoli VA, Kuettner KE: Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. J Natl Cancer Inst 67 (1): 65-73, 1981. [PUBMED Abstract] Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983. [PUBMED Abstract] Davis PF, He Y, Furneaux RH, et al.: Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvasc Res 54 (2): 178-82, 1997. [PUBMED Abstract] Sheu JR, Fu CC, Tsai ML, et al.: Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities. Anticancer Res 18 (6A): 4435-41, 1998 Nov-Dec. [PUBMED Abstract] McGuire TR, Kazakoff PW, Hoie EB, et al.: Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium. Pharmacotherapy 16 (2): 237-44, 1996 Mar-Apr. [PUBMED Abstract] Oikawa T, Ashino-Fuse H, Shimamura M, et al.: A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett 51 (3): 181-6, 1990. [PUBMED Abstract] Morris GM, Coderre JA, Micca PL, et al.: Boron neutron capture therapy of the rat 9L gliosarcoma: evaluation of the effects of shark cartilage. Br J Radiol 73 (868): 429-34, 2000. [PUBMED Abstract] Dupont E, Falardeau P, Mousa SA, et al.: Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin Exp Metastasis 19 (2): 145-53, 2002. [PUBMED Abstract] Béliveau R, Gingras D, Kruger EA, et al.: The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects. Clin Cancer Res 8 (4): 1242-50, 2002. [PUBMED Abstract] Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000. [PUBMED Abstract] Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999. [PUBMED Abstract] Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999. [PUBMED Abstract] Batist G, Champagne P, Hariton C, et al.: Dose-survival relationship in a phase II study of Neovastat in refractory renal cell carcinoma patients. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1907, 2002. Lu C, University of Texas - MD Anderson Cancer Center: Phase III Randomized Study of Induction Platinum-Based Chemotherapy and Radiotherapy With or Without Æ-941 (Neovastat) in Patients With Unresectable Stage IIIA or IIIB Non-Small Cell Lung Cancer, MDA-ID-99303, Clinical trial, Active. [PDQ Clinical Trial] Champagne P, Aeterna Laboratories, Incorporated: Phase III Randomized Study of AE-941 (Neovastat) in Patients With Metastatic Renal Cell Carcinoma Refractory to Immunotherapy, AETERNA-AE-RC-99-02, Clinical trial, Closed. [PDQ Clinical Trial] Loprinzi CL, North Central Cancer Treatment Group: Phase III Randomized Study of Shark Cartilage (BeneFin™) in Patients With Advanced Colorectal or Breast Cancer, NCCTG-971151, Clinical trial, Closed. [PDQ Clinical Trial] Champagne P, Aeterna Laboratories, Incorporated: Phase II Study of AE-941 (Neovastat) in Patients With Early Relapse or Refractory Multiple Myeloma, AETERNA-AE-MM-00-02, Clinical trial, Closed. [PDQ Clinical Trial] Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992. [PUBMED Abstract] Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994. [PUBMED Abstract] Li CY, Shan S, Huang Q, et al.: Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92 (2): 143-7, 2000. [PUBMED Abstract] Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994. Cremer MA, Rosloniec EF, Kang AH: The cartilage collagens: a review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease. J Mol Med 76 (3-4): 275-88, 1998. [PUBMED Abstract] Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988. [PUBMED Abstract] Houck JC, Jacob RA, DeAngelo L, et al.: The inhibition of inflammation and the acceleration of tissue repair by cartilage powder. Surgery 51: 632-38, 1962. Simone CB, Simone NL, Simone CB 2nd: Shark cartilage for cancer. Lancet 351 (9113): 1440, 1998. [PUBMED Abstract] Horsman MR, Alsner J, Overgaard J: The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma. Acta Oncol 37 (5): 441-5, 1998. [PUBMED Abstract] Read More On This Subject

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