Cartilage (Bovine and Shark) (PDQ®): Integrative, alternative, and complementary therapies - Health Professional Information [NCI]

Overview

NOTE: The information in this summary is no longer being updated and is provided for reference purposes only.

This cancer information summary provides an overview of the use of cartilage as a treatment for people with cancer. The summary includes a brief history of cartilage research, the results of clinical studies, and possible side effects of cartilage use.

This summary contains the following key information:

• Bovine (cow) cartilage and shark cartilage have been studied as treatments for people with cancer and other medical conditions for more than 30 years.
• Numerous cartilage products are sold commercially in the United States as dietary supplements.
• Three principal mechanisms of action have been proposed to explain the antitumor potential of cartilage: (1) it kills cancer cells directly; (2) it stimulates the immune system; and (3) it blocks the formation of new blood vessels (angiogenesis), which tumors need for unrestricted growth.
• At least three different inhibitors of angiogenesis have been identified in bovine cartilage, and two angiogenesis inhibitors have been purified from shark cartilage.
• Few human studies of cartilage as a treatment for people with cancer have been reported to date, and the results are inconclusive.
• Additional clinical trials of cartilage as a treatment for people with cancer are now being conducted.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

General Information

Bovine (cow) cartilage and shark cartilage have been investigated as treatments for people with cancer, psoriasis, arthritis, and a number of other medical conditions for more than 30 years.[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19] At least some of the interest in cartilage as a treatment for people with cancer arose from the mistaken belief that sharks, whose skeletons are made primarily of cartilage, are not affected by this disease.[16,20,21] Although reports of malignant tumors in sharks are rare, a variety of cancers have been detected in these animals.[20,21,22,23] Nonetheless, several substances that have antitumor activity have been identified in cartilage.[2,3,4,7,15,16,17,18,19,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49] More than half a dozen clinical studies of cartilage as a treatment for people with cancer have already been conducted.[2,3,4,6,7,8,9,15,16,17,18,49,50] Additional clinical studies, MDA-ID-99303 and AETERNA-AE-MM-00-02 have been completed.[6,15,50]

The absence of blood vessels in cartilage led to the hypothesis that cartilage cells (also known as chondrocytes) produce one or more substances that inhibit blood vessel formation.[27,28,29,30,35,36,48] 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.[33,34,41,51,52,53,54] 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.[53] Inhibition of angiogenesis at this early stage may, in some instances, lead to complete tumor regression.[53] The possibility that cartilage could be a source of one 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.[19,29,30,39,48,54,55]Chondroitin sulfate is the major glycosaminoglycan in cartilage.[39,54] 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 one angiogenesis inhibitor that has a glycosaminoglycan component (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information).[46] Other data indicate that most of the antiangiogenic activity in cartilage is not associated with the major structural components.[26,30,48]

Some glycosaminoglycans in cartilage reportedly have anti-inflammatory and immune-system -stimulating properties,[1,2,14,16,56,57] and it has been suggested that either they or some of their breakdown products are toxic to tumor cells.[2,3,24] Thus, the antitumor potential of cartilage may involve more than one 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.[17] In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the U.S. 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, it is unclear whether any of these products have 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.[17] The FDA has not approved the use of cartilage as a treatment for people with cancer or any other medical condition. The FDA is notifying consumers of a refund program for purchasers of Lane Labs-USA, Inc.'s shark cartilage product, BeneFin. Consumers are eligible for a partial refund of the purchase price and any shipping and handling costs if this product was purchased between September 22, 1999 and July 12, 2004.

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 four groups of investigators, one of which was the MDA-ID-99303 trial, that is now completed, to study cartilage as a treatment for people with cancer.[7,18,58] 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.[19,39,40,43,44,59,15,47] 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.[26,27,28,32,33,35,38,40,42,44,46,48] 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.[26,27,28,32,35,38,40,42,44,46,48]

In human studies (MDA-ID-99303, AETERNA-AE-MM-00-02, and NCCTG-971151), cartilage products have been administered topically or orally, or they have been given by enema or subcutaneous injection.[2,3,4,6,7,8,9,15,16,18,60] For oral administration, liquid, powdered, and pill forms have been used as described in the following completed trials: MDA-ID-99303, NCCTG-971151, AETERNA-AE-RC-99-02, and AETERNA-AE-MM-00-02.[2,3,4,6,7,8,9,15,16,18] 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:

1. 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.
2. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Iandoli R: Shark cartilage in the treatment of psoriasis. Dermatologia Clinica 21 (part 1): 39-42, 2001.
11. Milner M: A guide to the use of shark cartilage in the treatment of arthritis and other inflammatory joint diseases. American Chiropractor 21 (4): 40-2, 1999.
12. Himmel PB, Seligman TM: Treatment of systemic sclerosis with shark cartilage extract. Journal of Orthomolecular Medicine 14 (2): 73-7, 1999. Also available online. Last accessed April 8, 2016.
13. Sorbera LA, Castañer RM, Leeson PA: AE-941. Oncolytic, antipsoriatic, treatment of age-related macular degeneration, angiogenesis inhibitor. Drugs Future 25 (6): 551-7, 2000.
14. 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.
15. AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.
16. 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.
17. Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1 (6): 414-16, 1995.
18. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.
19. 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.
20. Ostrander GK, Cheng KC, Wolf JC, et al.: Shark cartilage, cancer and the growing threat of pseudoscience. Cancer Res 64 (23): 8485-91, 2004.
21. Finkelstein JB: Sharks do get cancer: few surprises in cartilage research. J Natl Cancer Inst 97 (21): 1562-3, 2005.
22. Schlumberger HG, Lucke B: Tumors of fishes, amphibians, and reptiles. Cancer Res 8 (12): 657-754, 1948.
23. Wellings SR: Neoplasia and primitive vertebrate phylogeny: echinoderms, prevertebrates, and fishes--A review. Natl Cancer Inst Monogr 31: 59-128, 1969.
24. 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.
25. 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.
26. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990.
27. 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.
28. Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr.
29. 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.
30. 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.
31. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977.
32. Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976.
33. 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.
34. 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.
35. 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.
36. 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.
37. 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.
38. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.
39. 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.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.
47. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.
48. Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999.
49. 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.
50. Loprinzi CL, Levitt R, Barton DL, et al.: Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Cancer 104 (1): 176-82, 2005.
51. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992.
52. Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994.
53. 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.
54. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
55. 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.
56. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.
57. 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.
58. Simone CB, Simone NL, Simone CB 2nd: Shark cartilage for cancer. Lancet 351 (9113): 1440, 1998.
59. 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.
60. Gingras D, Batist G, Béliveau R: AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. Expert Rev Anticancer Ther 1 (3): 341-7, 2001.

History

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.[1,2,3,4,5]

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.[1] The first report that bovine cartilage contains at least one angiogenesis inhibitor was published in the mid-1970s.[6] 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.[7,8,9,10]

The first report that shark cartilage contains at least one angiogenesis inhibitor was published in the early 1980s,[11] 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.[12] 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.[13] In addition, on a weight-for-weight basis, shark cartilage contains approximately 1,000 times more antiangiogenic activity than bovine cartilage.[11]

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.[14,15,16,17,18] Second, the activated endothelial cells must divide to produce new endothelial cells, which will be used to make the new blood vessels.[15,17,18,19,20] Third, the dividing endothelial cells must migrate toward the tumor.[15,16,17,18,19,20] 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.[18,19,20,21,22] 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,[23,24,25,26,27,28,29,30] 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.[33,34,35,36]

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976.
7. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
8. 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.
9. 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.
10. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.
11. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.
12. 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.
13. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.
14. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992.
15. Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994.
16. 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.
17. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
18. Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 15 (3): 180-9, 1997.
19. Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 103 (9): 1237-41, 1999.
20. 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.
21. McCawley LJ, Matrisian LM: Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6 (4): 149-56, 2000.
22. Mandal M, Mandal A, Das S, et al.: Clinical implications of matrix metalloproteinases. Mol Cell Biochem 252 (1-2): 305-29, 2003.
23. 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.
24. 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.
25. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977.
26. 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.
27. 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.
28. 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.
29. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.
30. Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999.
31. 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.
32. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.
33. 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.
34. Sigel MM, Fugmann RA: Studies on immunoglobulins reactive with tumor cells and antigens. Cancer Res 28 (7): 1457-9, 1968.
35. 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.
36. Pugliese PT, Heinerman J: Devour Disease with Shark Liver Oil. Green Bay, Wis: Impakt Communications, 1999.

Laboratory / Animal / Preclinical Studies

The antitumor potential of cartilage has been investigated extensively in laboratory and animal studies. Some of these studies have assessed the toxicity of cartilage products toward cancer cells in vitro.[1,2,3,4,5]

Powdered Cartilage Products

In one study, cells from 22 freshly isolated human tumors (nine ovary, three lung, two brain, two breast, and one each of sarcoma, melanoma, colon, pancreas, cervix, and testis) and three human cultured cell lines (breast cancer, colon cancer, and myeloma) were treated with Catrix, which is a commercially available powdered preparation of bovine (cow) cartilage.[1,3,4] In the study, the growth of all three cultured cell lines and cells from approximately 70% of the tumor specimens were inhibited by 50% or more when Catrix was used at high concentrations (1-5 mg /mL of culture fluid). However, it is unclear whether the inhibitory effect of Catrix in this study was specific to the growth of cancer cells because the preparation's effect on the growth of normal cells was not tested. In addition, the cytotoxic component of Catrix has not been identified, and it has not been shown that equivalent inhibitory concentrations of this component can be achieved in the bloodstreams of patients who may be treated with either injected or oral formulations of this product. (Refer to the Human/Clinical Studies section of this summary for more information.)

A commercially available preparation of powdered shark cartilage (no brand name given) was reported to have no effect on the growth of human astrocytoma cells in vitro.[2] The shark cartilage product tested in this study, however, was examined at only one concentration (0.75 mg/mL).[2]

The immune system -stimulating potential of cartilage has also been investigated in laboratory and animal studies.[6] In one study, Catrix was shown to stimulate the production of antibodies by mouse B cells (B lymphocytes) both in vitro and in vivo. However, increased antibody production in vivo was observed only when Catrix was administered by intraperitoneal or intravenous injection. It was not observed when oral formulations of Catrix were used.[6] In most experiments, the proliferation of mouse B cells (i.e., normal, nonmalignant cells) in vitro was increasingly inhibited as the concentration of Catrix was increased (tested concentration range, 1-20 mg/mL). Catrix has also been reported to stimulate the activity of mouse macrophages in vivo,[3] but results demonstrating this effect have not been published.

The effects of shark cartilage on the immune system were also reported in two studies that used the same purified protein fraction that had exhibited the most immunostimulatory effects when tested.[7,8] One study explored the effects of this fraction on tumor immune response by observing the infiltration of this fraction on CD4 and CD8 lymphocytes in a murine tumor model. An increase in the ratio of CD4/CD8 lymphocytes was seen in tumor-infiltrating lymphocytes but not in peripheral blood lymphocytes.[8] The second study exploring immune system response measured antibody response, cytotoxic assay, lymphocyte transformation, and intratumor T-cell ratio in mice. The fraction exhibited the ability to augment delayed-type hypersensitivity response against sheep red blood cells in mice and to decrease the cytotoxic activity of natural killer cells. In addition, this fraction showed a strong inhibitory effect on human brain microvascular endothelial cell proliferation and migration in the fibrin matrix.[7]

Additional in vivo studies of the antitumor potential of shark cartilage have been published in the peer-reviewed scientific literature.[9,10,11] In one study, oral administration of powdered shark cartilage (no brand name given) was shown to inhibit chemically induced angiogenesis in the mesenteric membrane of rats.[9] In another study, oral administration of powdered shark cartilage (no brand name given) was shown to reduce the growth of GS-9L gliosarcomas in rats.[10] It was reported in a third study that oral administration of two powdered shark cartilage products, Sharkilage and MIA Shark Powder, did not inhibit the growth or the metastasis of SCCVII squamous cell carcinomas in mice.[11]

A large number of laboratory and animal studies concerning the antiangiogenic potential of cartilage have been published.[2,9,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32] Overall, these studies have revealed the presence of at least three angiogenesis inhibitors in bovine cartilage [13,14,16,17,18,21,23,33] and at least two in shark cartilage.[2,9,25,26]

Aqueous Extracts of Cartilage

A liquid (i.e., aqueous) extract of shark cartilage called AE-941/Neovastat has also been reported to inhibit the growth of a variety of cancer cell types in vitro.[5] These results have not been published in a peer-reviewed scientific journal and are not consistent with other results obtained by the same group of investigators.[27,34]

Three angiogenesis inhibitors in bovine cartilage have been very well characterized.[13,14,16,17,18,21,23,33] They are relatively small proteins with molecular masses that range from 23,000 to 28,000.[13,14,16,23] These proteins, called cartilage-derived inhibitor (CDI), cartilage-derived antitumor factor (CATF), and cartilage-derived collagenase inhibitor (CDCI) by the researchers who purified them,[13,14,21] have been shown to block endothelial cell proliferation in vitro and new blood vessel formation in the chorioallantoic membrane of chicken embryos.[14,16,17,18,21,23,33] Two of the proteins (CDI and CDCI) have been shown to inhibit matrix metalloproteinase activity in vitro,[13,14,16,18] and one (CDI) has been shown to inhibit endothelial cell migration in vitro.[14,16] These proteins do not block the proliferation of normal cells or of tumor cells in vitro.[14,16,17,21,33] When the amino acid sequences of CDI, CATF, and CDCI were determined, it was discovered that they were the same as those of proteins known otherwise as tissue inhibitor of matrix metalloproteinases 1 (TIMP-1), chondromodulin I, and TIMP-2, respectively.[13,14,18,23,33]

A possible fourth angiogenesis inhibitor in bovine cartilage has been purified not from cartilage but from the culture fluid of bovine chondrocytes grown in the laboratory.[15] This inhibitor, which has been named chondrocyte-derived inhibitor (ChDI), is a protein that has a molecular mass of approximately 36,000. It has been reported that ChDI and CDI/TIMP-1 have similar antiangiogenic activities,[15,16,33] but the relationship between these proteins is unclear because amino acid sequence information for ChDI is not available. Thus, whether CDI/TIMP-1 is a breakdown product of ChDI or whether ChDI is truly the fourth angiogenesis inhibitor identified in bovine cartilage is unknown.

As indicated previously, shark cartilage, like bovine cartilage, contains more than one type of angiogenesis inhibitor. One shark cartilage inhibitor, named U-995, reportedly contains two small proteins, one with a molecular mass of approximately 14,000 and the other with a molecular mass of approximately 10,000.[25] Both proteins have shown antiangiogenic activity when tested individually. The exact relationship between these two proteins and their relationship to the larger bovine angiogenesis inhibitors are not known because amino acid sequence information for U-995 is not available. U-995 has been reported to inhibit endothelial cell proliferation, endothelial cell migration, matrix metalloproteinase activity in vitro, and the formation of new blood vessels in the chorioallantoic membrane of chicken embryos.[25] It does not appear to inhibit the proliferation of other types of normal cells or of cancer cells in vitro. Intraperitoneal but not oral administration of U-995 has been shown to inhibit the growth of mouse sarcoma-180 tumors implanted subcutaneously on the backs of mice and the formation of lung metastases of mouse B16-F10 melanoma cells injected into the tail veins of mice.[25]

The second angiogenesis inhibitor identified in shark cartilage appears to have been studied independently by three groups of investigators.[2,26,35] This inhibitor, which was named SCF2 by one of the groups,[35] is a proteoglycan that has a molecular mass of about 10,000. Proteoglycans are combinations of glycosaminoglycans and protein.[30] The principal glycosaminoglycan in SCF2 is keratan sulfate.[35] SCF2 has been shown to block endothelial cell proliferation in vitro,[2,26,35] the formation of new blood vessels in the chorioallantoic membrane of chicken embryos,[2,26] and tumor-induced angiogenesis in the corneas of rabbits.[2,26]

Other studies have demonstrated that AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, has antiangiogenic activity,[12,27,28,34,36,37,38,39] but the molecular basis for this activity has not been defined. Therefore, whether AE-941/Neovastat contains U-995 and/or SCF2 or some other angiogenesis inhibitor is not known. It has been reported that AE-941/Neovastat inhibits endothelial cell proliferation and matrix metalloproteinase activity in vitro and the formation of new blood vessels in the chorioallantoic membrane of chicken embryos.[12,27,31] In addition, AE-941/Neovastat has been shown to induce endothelial cell apoptosis by activating caspases, enzymes important in the promotion and regulation of apoptosis.[32,34,38] It also appears to inhibit the action of vascular endothelial growth factor, thus interfering with the communication between tumor cells and nearby blood vessels.[28,34,37,38] AE-941/Neovastat may also inhibit angiogenesis through promotion of tissue plasminogen activator (tPA) activity. Neovastat stimulates tPA expression in endothelial cells through an increase in the transcription of the tPA gene.[40] This transcriptional activation is associated with activation of c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-kappa B) signaling pathways to an extent similar to tumor necrosis factor-alpha (TNF-alpha).[40] Furthermore, AE-941/Neovastat has been reported to inhibit the growth of DA3 mammary adenocarcinoma cells and the metastasis of Lewis lung carcinoma cells in vivo in mice.[5,27,34,41] In the Lewis lung carcinoma experiments, AE-941/Neovastat enhanced the antimetastatic effect of the chemotherapy drug cisplatin.[5,27,34,41] All the aspects of preclinical development have been reviewed.[42]

The cartilage-derived antiangiogenic substance troponin I (TnI) has been isolated from human cartilage and has been produced by the cloning and expression of cDNA of human cartilage. It has been shown to specifically inhibit angiogenesis in vivo and in vitro and tumor metastasis in vivo.[43] The active site of Tnl has been located in the amino acid residues of 96 to 116. The synthetic peptide Glu94-Leu123 (pTnl) has been shown to be a potent inhibitor of endothelial cell tube formation and endothelial cell division and to inhibit pancreatic cancer metastases in an in vivo liver metastases model.[44]

References:

1. 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.
2. 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.
3. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
4. 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.
5. AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.
6. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.
7. Hassan ZM, Feyzi R, Sheikhian A, et al.: Low molecular weight fraction of shark cartilage can modulate immune responses and abolish angiogenesis. Int Immunopharmacol 5 (6): 961-70, 2005.
8. Feyzi R, Hassan ZM, Mostafaie A: Modulation of CD(4)(+) and CD(8)(+) tumor infiltrating lymphocytes by a fraction isolated from shark cartilage: shark cartilage modulates anti-tumor immunity. Int Immunopharmacol 3 (7): 921-6, 2003.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990.
15. 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.
16. Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr.
17. 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.
18. 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.
19. Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976.
20. 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.
21. 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.
22. 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.
23. 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.
24. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.
25. 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.
26. 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.
27. 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.
28. 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.
29. Cho J, Kim Y: Sharks: a potential source of antiangiogenic factors and tumor treatments. Mar Biotechnol (NY) 4 (6): 521-5, 2002.
30. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
31. Gingras D, Renaud A, Mousseau N, et al.: Matrix proteinase inhibition by AE-941, a multifunctional antiangiogenic compound. Anticancer Res 21 (1A): 145-55, 2001 Jan-Feb.
32. Boivin D, Gendron S, Beaulieu E, et al.: The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis. Mol Cancer Ther 1 (10): 795-802, 2002.
33. Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999.
34. 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.
35. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.
36. Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.
37. Gingras D, Batist G, Béliveau R: AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. Expert Rev Anticancer Ther 1 (3): 341-7, 2001.
38. Gingras D, Boivin D, Deckers C, et al.: Neovastat--a novel antiangiogenic drug for cancer therapy. Anticancer Drugs 14 (2): 91-6, 2003.
39. Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.
40. Gingras D, Nyalendo C, Di Tomasso G, et al.: Activation of tissue plasminogen activator gene transcription by Neovastat, a multifunctional antiangiogenic agent. Biochem Biophys Res Commun 320 (1): 205-12, 2004.
41. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.
42. Dredge K: AE-941 (AEterna). Curr Opin Investig Drugs 5 (6): 668-77, 2004.
43. Moses MA, Wiederschain D, Wu I, et al.: Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci U S A 96 (6): 2645-50, 1999.
44. Kern BE, Balcom JH, Antoniu BA, et al.: Troponin I peptide (Glu94-Leu123), a cartilage-derived angiogenesis inhibitor: in vitro and in vivo effects on human endothelial cells and on pancreatic cancer. J Gastrointest Surg 7 (8): 961-8; discussion 969, 2003.

Human / Clinical Studies

Since the early 1970s, at least a dozen clinical trials (MDA-ID-99303, NCCTG-971151, and AETERNA-AE-MM-00-02) of cartilage as a treatment for people with cancer have been (or are being) conducted;[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15] (refer to the table at the end of this section) however, results from only seven studies have been published in peer-reviewed scientific journals.[1,2,4,8,9,16] It is not clear whether any of the patients in these studies were children.

In the first randomized trial published in a peer-reviewed scientific journal, 83 incurable breast cancer and colorectal cancer patients were randomly assigned to receive either shark cartilage or placebo, in addition to standard care. No difference was observed in survival or quality of life between those receiving shark cartilage and those receiving placebo.[8] Additional clinical studies are under way; however, the cumulative evidence to date is inconclusive regarding the effectiveness of cartilage as a treatment for people with cancer.

Powdered Cartilage Products

Two of the three published clinical studies evaluated the use of Catrix, the previously mentioned (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information) powdered preparation of bovine (cow) cartilage, as a treatment for various solid tumors.[1,2] One of these studies was a case series that included 31 patients;[1] the other was a phase II clinical trial that included 9 patients.[2]

In the case series,[1] all patients were treated with subcutaneously injected and/or oral Catrix; however, three patients (one with squamous cell carcinoma of the skin and two with basal cell carcinoma of the skin) were also treated with topical preparations. The individual dose, the total dose, and the duration of Catrix treatment in this series varied from patient to patient; however, the minimum treatment duration was 7 months, and the maximum duration was more than 10 years. Eighteen patients had been treated with conventional therapy (surgery, chemotherapy, radiation therapy, hormonal therapy) within 1 year of the start of Catrix treatment; nine patients received conventional therapy concurrently with Catrix treatment; and seven patients received conventional therapy both prior to and during Catrix treatment. It was reported that 19 patients had a complete response, 10 patients had a partial response, and 1 patient had stable disease following Catrix treatment. The remaining patient did not respond to cartilage therapy. Eight of the patients with a complete response received no prior or concurrent conventional therapy. Approximately half of the patients with a complete response eventually experienced recurrent cancer.

This clinical study had several weaknesses that could have affected its outcome, including the absence of a control group and the receipt of prior and/or concurrent conventional therapy by most patients.

Partial results of a third clinical study of Catrix are described in an abstract submitted for presentation at a scientific conference,[3] but complete results of this study have not been published in a peer-reviewed scientific journal. In the study, 35 patients with metastatic renal cell carcinoma were divided into four groups, and the individuals in each group were treated with identical doses of subcutaneously injected and/or oral Catrix. Three partial responses and no complete responses were observed among 22 evaluable patients who were treated with Catrix for more than 3 months. Following Catrix therapy, 2 of the 22 evaluable patients were reported to have stable disease, and 17 were reported to have progressive disease. No relationship between Catrix dose and tumor response could be established in this study.

The third published study of cartilage as a treatment for people with cancer was a phase I/II trial that tested the safety and the efficacy of orally administered Cartilade, a commercially available powdered preparation of shark cartilage, in 60 patients with various types of advanced solid tumors.[4] All but one patient in this trial had been treated previously with conventional therapy. According to the design of the study, no additional anticancer treatment could be given concurrently with Cartilade therapy. No complete responses or partial responses were observed among 50 evaluable patients who were treated with Cartilade for at least 6 weeks. However, stable disease that lasted 12 weeks or more was reported for 10 of the 50 patients. All ten of these patients eventually experienced progressive disease.

Partial results of three other clinical studies of powdered shark cartilage are described in two abstracts submitted for presentation at scientific conferences,[5,6] but complete results of these studies have not been published in peer-reviewed scientific journals. All three studies were phase II clinical trials that involved patients with advanced disease; two of the studies were conducted by the same group of investigators.[5] These three studies enrolled 20 patients with breast cancer,[5] 12 patients with prostate cancer,[5] and 12 patients with primary brain tumors.[6] All patients had been treated previously with conventional therapy. No other anticancer treatment was allowed concurrently with cartilage therapy. In two of the studies,[5] the name of the cartilage product was not identified; however, in the third study,[6] the commercially available product BeneFin was used. Ten patients in each study completed at least 8 weeks of treatment and therefore were considered evaluable for response. No complete responses or partial responses were observed in any of the studies. Two evaluable patients in the breast cancer study were reported to have stable disease that lasted 8 weeks or more; two evaluable patients in the brain tumor study had stable disease that lasted 20 weeks or more; and three evaluable patients in the prostate cancer study had stable disease that also lasted 20 weeks or more.

Aqueous Extracts of Cartilage

In the phase II trial,[2] Catrix was administered by subcutaneous injection only. All patients in this trial had progressive disease following radiation therapy and/or chemotherapy. Identical individual doses of Catrix were administered to each patient, but the duration of treatment and the total delivered dose varied because of disease progression or death. The minimum duration of Catrix treatment in this study was 4 weeks. One patient (with metastatic renal cell carcinoma) reportedly had a complete response that lasted more than 39 weeks. The remaining eight patients did not respond to Catrix treatment. The researchers in this trial also investigated whether Catrix had an effect on immune system function in these patients. No consistent trend or change in the numbers, percentages, or ratios of white blood cells (i.e., total lymphocyte counts, total T cell counts, total B cell counts, percentage of T cells, percentage of B cells, and ratio of helper T cells to cytotoxic T cells) was observed, though increased numbers of T cells were found in three patients.

The safety and the efficacy of AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, has also been examined in clinical studies.[9,10,11,15,17] It has been reported that AE-941/Neovastat has little toxicity.[10,11,15] In addition, there is evidence from a randomized clinical trial that examined the effect of AE-941/Neovastat on angiogenesis associated with surgical wound repair that this product contains at least one antiangiogenic component that is orally bioavailable.[17]

AE-941/Neovastat was administered to 331 patients with advanced solid tumors (including lung, prostate, breast, and kidney tumors) in two phase I/II trials.[10] The results of these trials, however, have not been fully reported. A retrospective analysis involving a subgroup of patients with advanced non-small cell lung cancer (NSCLC) suggests that AE-941/Neovastat is able to lengthen the survival of patients with this disease.[10] Furthermore, in a prospective analysis involving 22 patients with refractory renal cell carcinoma, survival was longer in patients treated with 240 mL /day AE-941/Neovastat than in patients treated with only 60 mL/day.[7,10,16]

In 2003, the results of a phase I/II trial of AE-941/Neovastat in 80 patients with advanced NSCLC reported that there was a significant survival advantage for patients receiving the highest doses (2.6 mL/kg/day) of AE-941/Neovastat. A survival analysis of 48 patients with unresectable stage IIIA, IIIB, or IV NSCLC showed a median survival advantage of P = .0026 in patients receiving the highest doses. The trial was principally conducted to explore the safety and efficacy of orally administered AE-941/Neovastat when administered in escalating doses (30, 60, 120, and 240 mL/day). No dose-limiting toxicity was found, and no tumor response was observed.[9]

In 2001, a phase II trial (AETERNA-AE-MM-00-02) of AE-941/Neovastat was initiated in patients with relapsed or refractory multiple myeloma. This trial closed approximately 1 year later, and no results have been reported.[18]

Two randomized phase III trials of AE-941/Neovastat in patients with advanced cancer have been approved by the U.S. Food and Drug Administration (FDA). In one trial (MDA-ID-99303), which is completed, treatment with oral AE-941/Neovastat plus chemotherapy and radiation therapy was compared with treatment with placebo plus the same chemotherapy and radiation therapy in patients with stage III NSCLC. In the second trial, which closed to patient recruitment in 2002, treatment with oral AE-941/Neovastat was compared with treatment with placebo in patients with metastatic renal cell carcinoma. Results from this second phase III trial have not been reported in the peer-reviewed scientific literature.[19] Despite AE-941/Neovastat being granted orphan drug status by the FDA in 2002 for use in the treatment of renal cell carcinoma, the company that produces AE-941/Neovastat, Aeterna Laboratories, announced in early 2004 that this application would be discontinued in favor of a focus on the treatment of NSCLC.[19,20]

In 2010, the results of a randomized, double-blind, placebo-controlled phase III trial aimed at assessing the effect of adding AE-941 to chemotherapy and radiation therapy on the overall survival of patients with nonresectable stage III NSCLC were reported. A total of 379 eligible patients received induction chemotherapy followed by concurrent chemotherapy with chest radiation therapy; participating centers used one of two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. No statistically significant difference in overall survival was observed between the group (n = 188) receiving chemotherapy and radiation therapy plus AE-941 (120 mL administered orally twice daily) and the group receiving chemotherapy and radiation therapy plus placebo (n = 191). Both AE-941 and placebo were well tolerated.[21]

References:

1. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Loprinzi CL, Levitt R, Barton DL, et al.: Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Cancer 104 (1): 176-82, 2005.
9. Latreille J, Batist G, Laberge F, et al.: Phase I/II trial of the safety and efficacy of AE-941 (Neovastat) in the treatment of non-small-cell lung cancer. Clin Lung Cancer 4 (4): 231-6, 2003.
10. 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.
11. AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.
12. 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.
13. Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1 (6): 414-16, 1995.
14. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.
15. AE 941. Drugs R D 5 (2): 83-9, 2004.
16. Batist G, Patenaude F, Champagne P, et al.: Neovastat (AE-941) in refractory renal cell carcinoma patients: report of a phase II trial with two dose levels. Ann Oncol 13 (8): 1259-63, 2002.
17. Berbari P, Thibodeau A, Germain L, et al.: Antiangiogenic effects of the oral administration of liquid cartilage extract in humans. J Surg Res 87 (1): 108-13, 1999.
18. Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.
19. Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.
20. New treatment option for postmenopausal women with early breast cancer. Expert Rev Anticancer Ther 2 (6): 617, 2002.
21. Lu C, Lee JJ, Komaki R, et al.: Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. J Natl Cancer Inst 102 (12): 859-65, 2010.

Adverse Effects

The side effects associated with cartilage therapy are generally described as mild to moderate in severity. Inflammation at injection sites, dysgeusia, fatigue, nausea, dyspepsia, fever, dizziness, and edema of the scrotum have been reported after treatment with the bovine (cow) cartilage product Catrix.[1,2,3] Nausea, vomiting, abdominal cramping and/or bloating, constipation, hypotension, hyperglycemia, generalized weakness, and hypercalcemia have been associated with the use of powdered shark cartilage.[4,5,6] The high level of calcium in shark cartilage may contribute to the development of hypercalcemia.[5,7] In addition, one case of hepatitis has been associated with the use of powdered shark cartilage.[8] Nausea, vomiting, and dyspepsia are the most commonly reported side effects following treatment with AE-941/Neovastat, the aqueous extract of shark cartilage.[9]

References:

1. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Jungi WF: Dangerous nutrition. Support Care Cancer 11 (4): 197-8, 2003.
8. Ashar B, Vargo E: Shark cartilage-induced hepatitis. Ann Intern Med 125 (9): 780-1, 1996.
9. 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.

Summary of the Evidence for Cartilage

Although at least a dozen clinical studies of cartilage as a treatment for people with cancer have been conducted since the early 1970s, relatively few results have been reported in the peer-reviewed scientific literature. There are small amounts of reported data from phase III clinical trials. Additional clinical studies are now under way. At present, the use of cartilage (bovine [cow] or shark) as a treatment for people with cancer cannot be recommended outside the context of well-designed clinical trials.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Changes to This Summary (07 / 21 / 2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of cartilage (bovine and shark) in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Cartilage (Bovine and Shark) are:

• John A. Beutler, PhD (National Cancer Institute)
• Keith I. Block, MD (Block Center for Integrative Cancer Treatment & University of Illinois College of Medicine)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Cartilage (Bovine and Shark). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/cartilage-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389205]

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Last Revised: 2016-07-21