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Cartilage (Bovine and Shark) (PDQ®)     
Last Modified: 04/17/2008
Health Professional Version
Table of Contents

Purpose of This PDQ Summary
Overview
General Information
History
Laboratory/Animal/Preclinical Studies
Human/Clinical Studies
Adverse Effects
Overall Level of Evidence for Cartilage
Changes to This Summary (04/17/2008)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of cartilage as a treatment for cancer. The summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board 1.

Information about the following is included in this summary:

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level of evidence designation. These designations are intended to help the readers assess the strength of the evidence supporting the use of specific interventions or treatment strategies. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system 2 in developing its level of evidence designations. These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version 3, which is written in less technical language.

Overview

This complementary and alternative medicine (CAM) information summary provides an overview of the use of cartilage as a treatment for 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 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 cancer have been reported to date, and the results are inconclusive.
  • Additional clinical trials of cartilage as a treatment for 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 Web site Dictionary 4, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window. All linked terms and their corresponding definitions will appear in a glossary in the printable version of the summary.

Reference citations in some PDQ CAM information summaries may include links to external Web sites 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 Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute (NCI).

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.[1-13] Reviewed in [14-20] 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 [16,21,22] Although reports of malignant tumors in sharks are rare, a variety of cancers have been detected in these animals. Reviewed in [21-24] Nonetheless, several substances that have antitumor activity have been identified in cartilage.[25-47] Reviewed in [2-4,7,15-20,46,48-50] More than half a dozen clinical studies of cartilage as a treatment for cancer have already been conducted,[2-4,7-9,50,51] Reviewed in [6,15-19] and additional clinical studies (MDA-ID-99303 5 and AETERNA-AE-MM-00-02 6) are now under way. Reviewed in [6,15,51]

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. Reviewed in [28-31,36,37,49] 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 [34,35,42,52-55] 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.[54] Inhibition of angiogenesis at this early stage may, in some instances, lead to complete tumor regression.[54] 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. Reviewed in [20,30,31,40,49,55,56] Chondroitin sulfate is the major glycosaminoglycan in cartilage. Reviewed in [40,55] 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 7 section of this summary for more information).[47] Other data indicate that most of the antiangiogenic activity in cartilage is not associated with the major structural components. Reviewed in [27,31,49]

Some glycosaminoglycans in cartilage reportedly have anti-inflammatory and immune-system –stimulating properties,[57,58] Reviewed in [1,2,14,16] and it has been suggested that either they or some of their breakdown products are toxic to tumor cells.[25] Reviewed in [2,3] 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. Reviewed in [18] 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, Reviewed in [18] 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 [18] The FDA has not approved the use of cartilage as a treatment for cancer or any other medical condition. The FDA is notifying consumers of a refund program for purchasers of Lane Labs-USA, Inc.'s, BeneFin, its shark cartilage product. 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 is the MDA-ID-99303 trial, to study cartilage as a treatment for cancer. [7,59] Reviewed in [19] 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.[20,40,41,44,45,60] Reviewed in [15,48] 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.[27,28,33,34,36,39,41,43,45] Reviewed in [29,47,49] 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.[27,28,33,36,39,41,43,45] Reviewed in [29,47,49]

In human studies (MDA-ID-99303, AETERNA-AE-MM-00-02, and NCCTG-971151 8), cartilage products have been administered topically or orally, or they have been given by enema or subcutaneous injection.[2-4,7-9] Reviewed in AETERNA-AE-RC-99-02 9,[6,15-17,19,61] For oral administration, liquid, powdered, and pill forms have been used as described in MDA-ID-99303, NCCTG-971151, and AETERNA-AE-MM-00-02.[2-4,7-9] Reviewed in [6,15-17,19] 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.  [PUBMED Abstract]

  2. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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. 10 Last accessed October 30, 2008. 

  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.  [PUBMED Abstract]

  15. AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.  [PUBMED Abstract]

  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. Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. 11 Last accessed October 30, 2008. 

  18. Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1: 414-16, 1995. 

  19. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.  [PUBMED Abstract]

  20. 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]

  21. Ostrander GK, Cheng KC, Wolf JC, et al.: Shark cartilage, cancer and the growing threat of pseudoscience. Cancer Res 64 (23): 8485-91, 2004.  [PUBMED Abstract]

  22. Finkelstein JB: Sharks do get cancer: few surprises in cartilage research. J Natl Cancer Inst 97 (21): 1562-3, 2005.  [PUBMED Abstract]

  23. Schlumberger HG, Lucke B: Tumors of fishes, amphibians, and reptiles. Cancer Res 8: 657-754, 1948. 

  24. Wellings SR: Neoplasia and primitive vertebrate phylogeny: echinoderms, prevertebrates, and fishes--A review. Natl Cancer Inst Monogr 31: 59-128, 1969.  [PUBMED Abstract]

  25. 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]

  26. 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]

  27. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990.  [PUBMED Abstract]

  28. 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]

  29. Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr.  [PUBMED Abstract]

  30. 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]

  31. 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]

  32. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977.  [PUBMED Abstract]

  33. 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]

  34. 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]

  35. 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]

  36. 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]

  37. 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]

  38. 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]

  39. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.  [PUBMED Abstract]

  40. 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]

  41. 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]

  42. 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]

  43. 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]

  44. 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]

  45. 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]

  46. 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]

  47. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.  [PUBMED Abstract]

  48. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.  [PUBMED Abstract]

  49. 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]

  50. 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. 

  51. 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.  [PUBMED Abstract]

  52. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992.  [PUBMED Abstract]

  53. Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994.  [PUBMED Abstract]

  54. 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]

  55. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994. 

  56. 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]

  57. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.  [PUBMED Abstract]

  58. 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. 

  59. Simone CB, Simone NL, Simone CB 2nd: Shark cartilage for cancer. Lancet 351 (9113): 1440, 1998.  [PUBMED Abstract]

  60. 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]

  61. Gingras D, Batist G, Béliveau R: AE-941 (Neovastat): a novel multifunctional antiangiogenic compound. Expert Rev Anticancer Ther 1 (3): 341-7, 2001.  [PUBMED Abstract]

History

The therapeutic potential of cartilage has been investigated for more than 30 years. As noted previously (General Information 12), cartilage products have been tested as treatments for cancer, psoriasis, and arthritis. Cartilage products have also been studied as enhancers of wound repair and as treatments for osteoporosis, ulcerative colitis, regional enteritis, acne, scleroderma, hemorrhoids, severe anal itching, and the dermatitis caused by poison oak and poison ivy.[1] Reviewed in [2-5]

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.[7-10]

In contrast, 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 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. Reviewed in [13] In addition, on a weight-for-weight basis, shark cartilage contains approximately 1,000 times more antiangiogenic activity than bovine cartilage.[11] Reviewed in [14]

As indicated previously (Overview 13 and General Information 12), 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 7 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. Reviewed in [15-19] Second, the activated endothelial cells must divide to produce new endothelial cells, which will be used to make the new blood vessels. Reviewed in [16,18-21] Third, the dividing endothelial cells must migrate toward the tumor. Reviewed in [16-21] 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. Reviewed in [19-23] Fourth, the new endothelial cells must form the hollow tubes that will become the new blood vessels. Reviewed in [18,19] Some angiogenesis inhibitors may be able to block more than one step in this process.

Cartilage is relatively resistant to invasion by tumor cells, Reviewed in [24-31] and tumor cells use matrix metalloproteinases when they migrate during the process of metastasis. Reviewed in [14,22,26,32,33] 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.[34-36] Reviewed in [37]

Learn more about angiogenesis 14.

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: 632-38, 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  6. 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]

  7. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  10. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.  [PUBMED Abstract]

  11. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  13. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.  [PUBMED Abstract]

  14. Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. 11 Last accessed October 30, 2008. 

  15. Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992.  [PUBMED Abstract]

  16. Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994.  [PUBMED Abstract]

  17. 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]

  18. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994. 

  19. Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 15 (3): 180-9, 1997.  [PUBMED Abstract]

  20. Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 103 (9): 1237-41, 1999.  [PUBMED Abstract]

  21. 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]

  22. McCawley LJ, Matrisian LM: Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6 (4): 149-56, 2000.  [PUBMED Abstract]

  23. Mandal M, Mandal A, Das S, et al.: Clinical implications of matrix metalloproteinases. Mol Cell Biochem 252 (1-2): 305-29, 2003.  [PUBMED Abstract]

  24. 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]

  25. 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]

  26. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977.  [PUBMED Abstract]

  27. 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]

  28. 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]

  29. 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]

  30. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.  [PUBMED Abstract]

  31. 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]

  32. 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]

  33. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.  [PUBMED Abstract]

  34. 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]

  35. Sigel MM, Fugmann RA: Studies on immunoglobulins reactive with tumor cells and antigens. Cancer Res 28 (7): 1457-9, 1968.  [PUBMED Abstract]

  36. 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]

  37. 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] Reviewed in [3-6]

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] Reviewed in [3,4,6] In the study, the growth of all three cultured cell lines and of cells from approximately 70% of the tumor specimens was inhibited by 50% or more when Catrix was used at high concentrations (1–5 mg /mL of culture fluid). It is unclear, however, 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 15 section of this summary for more information.)

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. Reviewed in [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.[7,8]

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.[9] 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.[9] 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, Reviewed in [3,6] 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.[10,11] One study explored the effects of this fraction on tumor immune response by observing the infiltration of this fraction on CD=4 and CD=8 lymphocytes in a murine tumor model. An increase in the ratio of CD=4/CD=8 lymphocytes was seen in tumor-infiltrating lymphocytes but not in peripheral blood lymphocytes.[11] 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.[10]

A large number of laboratory and animal studies have been published concerning the antiangiogenic potential of cartilage.[2,12-27,8,28-32] Overall, these studies have revealed the presence of at least three angiogenesis inhibitors in bovine cartilage [13,14,17,18,21,23] Reviewed in [16,33] and at least two in shark cartilage.[2,25-27]

Three angiogenesis inhibitors in bovine cartilage have been very well characterized.[13,14,17,18,21,23] Reviewed in [16,33] They are relatively small proteins with molecular masses that range from 23,000 to 28,000.[13,14,23] Reviewed in [16] 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.[14,17,18,21,23] Reviewed in [16,33] Two of the proteins (CDI and CDCI) have been shown to inhibit matrix metalloproteinase activity in vitro,[13,14,18] Reviewed in [16] and one CDI has been shown to inhibit endothelial cell migration in vitro.[14] Reviewed in [16] These proteins do not block the proliferation of normal cells or of tumor cells in vitro.[14,17,21] Reviewed in [16,33] 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 (ChMI), and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2), respectively.[13,14,18,23] Reviewed in [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.[15] It has been reported that ChDI and CDI/TIMP-1 have similar antiangiogenic activities,[15] Reviewed in [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.[26] Both proteins have shown antiangiogenic activity when tested individually.[26] The exact relationship between these two proteins, and their relationship to the larger bovine angiogenesis inhibitors is 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.[26] It does not appear to inhibit the proliferation of other types of normal cells or of cancer cells in vitro.[26] 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.[26]

The second angiogenesis inhibitor identified in shark cartilage appears to have been studied independently by three groups of investigators.[2,27,34] This inhibitor, which was named SCF2 by one of the groups,[34] is a proteoglycan that has a molecular mass of about 10,000. Proteoglycans are combinations of glycosaminoglycans and protein. Reviewed in [30] The principal glycosaminoglycan in SCF2 is keratan sulfate.[34] SCF2 has been shown to block endothelial cell proliferation in vitro,[2,27,34] the formation of new blood vessels in the chorioallantoic membrane of chicken embryos,[2,27] and tumor-induced angiogenesis in the cornea of rabbits.[2,27]

Other studies have demonstrated that AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, has antiangiogenic activity,[8,12,28] Reviewed in [7,35-38] 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.[8,12,31] 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] Reviewed in [7,37] 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] Reviewed in [7,36,37] It 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.[39] 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).[39] 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.[8] Reviewed in [5,7,40] In the Lewis lung carcinoma experiments, AE-941/Neovastat enhanced the antimetastatic effect of the chemotherapy drug cisplatin.[8] Reviewed in [5,7,40] All the aspects of preclinical development have been reviewed.[41]

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 as well as tumor metastasis in vivo.[42] 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.[43]

Additional in vivo studies of the antitumor potential of shark cartilage have been published in the peer-reviewed scientific literature.[25,44,45] 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.[25] 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.[44] In contrast, 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.[45]

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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  3. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  5. AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.  [PUBMED Abstract]

  6. Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. 11 Last accessed October 30, 2008. 

  7. 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]

  8. 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]

  9. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.