The therapeutic potential of cartilage has been investigated for more than 30 years. As noted previously (refer to the General Information section of this summary for more information), cartilage products have been tested as treatments for people with cancer, psoriasis, and arthritis. Cartilage products have also been studied as enhancers of wound repair and as treatments for people with osteoporosis, ulcerative colitis, regional enteritis, acne, scleroderma, hemorrhoids, severe anal itching, and the dermatitis caused by poison oak and poison ivy.[1-5]
Early studies of cartilage’s therapeutic potential utilized extracts of bovine (cow) cartilage. The ability of these extracts to suppress inflammation was first described in the early 1960s. The first report that bovine cartilage contains at least one angiogenesis inhibitor was published in the mid-1970s. The use of bovine cartilage extracts to treat patients with cancer and the ability of these extracts to kill cancer cells directly and to stimulate animal immune systems were first described in the mid- to late-1980s.[7-10]
The first report that shark cartilage contains at least one angiogenesis inhibitor was published in the early 1980s, and the only published report to date of a clinical trial of shark cartilage as a treatment for people with cancer appeared in the late 1990s. The more recent interest in shark cartilage is due, in part, to the greater abundance of cartilage in this animal and its apparently higher level of antiangiogenic activity. Approximately 6% of the body weight of a shark is composed of cartilage, compared with less than 1% of the body weight of a cow. In addition, on a weight-for-weight basis, shark cartilage contains approximately 1,000 times more antiangiogenic activity than bovine cartilage.
As indicated previously (refer to the Overview and General Information sections of this summary for more information), at least three different mechanisms of action have been proposed to explain the anticancer potential of cartilage: 1) it is toxic to cancer cells; 2) it stimulates the immune system; and 3) it inhibits angiogenesis. Only limited evidence is available to support the first two mechanisms of action; however, the evidence in favor of the third mechanism is more substantial (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information).
The process of angiogenesis requires at least four coordinated steps, each of which may be a target for inhibition. First, tumors must communicate with the endothelial cells that line the inside of nearby blood vessels. This communication takes place, in part, through the secretion of angiogenesis factors such as vascular endothelial growth factor.[14-18] Second, the activated endothelial cells must divide to produce new endothelial cells, which will be used to make the new blood vessels.[15,17-20] Third, the dividing endothelial cells must migrate toward the tumor.[15-20] To accomplish this, they must produce enzymes called matrix metalloproteinases, which will help them carve a pathway through the tissue elements that separate them from the tumor.[18-22] Fourth, the new endothelial cells must form the hollow tubes that will become the new blood vessels.[17,18] Some angiogenesis inhibitors may be able to block more than one step in this process.
Cartilage is relatively resistant to invasion by tumor cells,[23-30] and tumor cells use matrix metalloproteinases when they migrate during the process of metastasis.[21,25,31,32] Therefore, if the angiogenesis inhibitors in cartilage are also inhibitors of matrix metalloproteinases, then the same molecules may be able to block both angiogenesis and metastasis. Shark tissues other than cartilage have also been reported to produce antitumor substances.[33-36]
- Houck JC, Jacob RA, Deangelo L, et al.: The inhibition of inflammation and the acceleration of tissue repair by cartilage powder. Surgery 51: 632-8, 1962. [PUBMED Abstract]
- 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, 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]
- 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.
- 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]
- 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]
- 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]
- 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]
- Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988. [PUBMED Abstract]
- Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983. [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]
- Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995. [PUBMED Abstract]
- 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.
- Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 15 (3): 180-9, 1997. [PUBMED Abstract]
- Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 103 (9): 1237-41, 1999. [PUBMED Abstract]
- Haas TL, Madri JA: Extracellular matrix-driven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc Med 9 (3-4): 70-7, 1999 Apr-May. [PUBMED Abstract]
- McCawley LJ, Matrisian LM: Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6 (4): 149-56, 2000. [PUBMED Abstract]
- Mandal M, Mandal A, Das S, et al.: Clinical implications of matrix metalloproteinases. Mol Cell Biochem 252 (1-2): 305-29, 2003. [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]
- 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]
- 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]
- Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000. [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]
- 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]
- Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999. [PUBMED Abstract]
- Pettit GR, Ode RH: Antineoplastic agents L: isolation and characterization of sphyrnastatins 1 and 2 from the hammerhead shark Sphyrna lewini. J Pharm Sci 66 (5): 757-8, 1977. [PUBMED Abstract]
- Sigel MM, Fugmann RA: Studies on immunoglobulins reactive with tumor cells and antigens. Cancer Res 28 (7): 1457-9, 1968. [PUBMED Abstract]
- Snodgrass MJ, Burke JD, Meetz GD: Inhibitory effect of shark serum on the Lewis lung carcinoma. J Natl Cancer Inst 56 (5): 981-4, 1976. [PUBMED Abstract]
- Pugliese PT, Heinerman J: Devour Disease with Shark Liver Oil. Green Bay, Wis: Impakt Communications, 1999.