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:

• A brief history of cartilage research.
• The results of clinical studies of cartilage.
• Possible side effects of cartilage use.

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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
14. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
16. Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
19. 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]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
24. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.  [PUBMED Abstract]
    
    
25. 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]
    
    
26. 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]
    
    
27. 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]
    
    
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.  [PUBMED Abstract]
    
    
29. Cho J, Kim Y: Sharks: a potential source of antiangiogenic factors and tumor treatments. Mar Biotechnol (NY) 4 (6): 521-5, 2002.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
33. 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]
    
    
34. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.  [PUBMED Abstract]
    
    
35. Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.  [PUBMED Abstract]
    
    
36. 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]
    
    
37. Gingras D, Boivin D, Deckers C, et al.: Neovastat--a novel antiangiogenic drug for cancer therapy. Anticancer Drugs 14 (2): 91-6, 2003.  [PUBMED Abstract]
    
    
38. Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.  [PUBMED Abstract]
    
    
39. 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.  [PUBMED Abstract]
    
    
40. Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.  [PUBMED Abstract]
    
    
41. Dredge K: AE-941 (AEterna). Curr Opin Investig Drugs 5 (6): 668-77, 2004.  [PUBMED Abstract]
    
    
42. 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.  [PUBMED Abstract]
    
    
43. 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.  [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. 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]
    
    

Human/Clinical Studies

At least a dozen clinical studies (MDA-ID-99303 ⁵, NCCTG-971151 ⁸, and AETERNA-AE-MM-00-02 ⁶) of cartilage as a treatment for cancer have been, or are being, conducted since the early 1970s;[1-9] Reviewed in [10-16] (see the table ¹⁶ at the end of this section) however, results from only six studies have been published in peer-reviewed scientific journals.[1,2,4,8,9,17] It is not clear whether any of the patients in the conducted studies were children.

In the only 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 cancer treatment.

Two of the three published clinical studies evaluated the use of Catrix, the previously mentioned (Laboratory/Animal/Preclinical Studies ⁷) 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 nine 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 treated with topical preparations as well. 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 (at the same time) 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, ten patients had a partial response, and one 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.

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.

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. Two of the 22 evaluable patients were reported to have stable disease and 17 were reported to have progressive disease following Catrix therapy. No relationship could be established between Catrix dose and tumor response in this study.

The third published study of cartilage as a treatment for 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.

The safety and the efficacy of AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, have also been examined in clinical studies.[9,18] Reviewed in [11,10,16] It has been reported that AE-941/Neovastat has little toxicity. Reviewed in [10,11,16] 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.[18]

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. Reviewed in [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 suggests that AE-941/Neovastat is able to lengthen the survival of patients with this disease. Reviewed in [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.[7,17] Reviewed in [10]

In 2003, the results of a phase I/II trial of AE-941/Neovastat in 80 patients with advanced non-small cell lung cancer (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. 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.[19]

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.[20] Despite being granted orphan drug status by the FDA in 2002 for use of AE-941/Neovastat 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.[20,21]

References

1. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
11. AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.  [PUBMED Abstract]
    
    
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. Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. ¹¹ Last accessed October 30, 2008. 
    
    
14. Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1: 414-16, 1995. 
    
    
15. Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.  [PUBMED Abstract]
    
    
16. AE 941. Drugs R D 5 (2): 83-9, 2004.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.  [PUBMED Abstract]
    
    
20. Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.  [PUBMED Abstract]
    
    
21. New treatment option for postmenopausal women with early breast cancer. Expert Rev Anticancer Ther 2 (6): 617, 2002.  [PUBMED Abstract]
    
    

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.[1-3] Nausea, vomiting, abdominal cramping and/or bloating, constipation, hypotension, hyperglycemia, generalized weakness, and hypercalcemia have been associated with the use of powdered shark cartilage.[4-6] The high level of calcium in shark cartilage may contribute to the development of hypercalcemia. Reviewed in [5,7,8] In addition, one case of hepatitis has been associated with the use of powdered shark cartilage.[9] Nausea, vomiting, and dyspepsia are the most commonly reported side effects following treatment with AE-941/Neovastat, the aqueous extract of shark cartilage. Reviewed in [10]

References

1. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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. Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. ¹¹ Last accessed October 30, 2008. 
   
   
8. Jungi WF: Dangerous nutrition. Support Care Cancer 11 (4): 197-8, 2003.  [PUBMED Abstract]
   
   
9. Ashar B, Vargo E: Shark cartilage-induced hepatitis. Ann Intern Med 125 (9): 780-1, 1996.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    

Overall Level of Evidence for Cartilage

Although at least a dozen clinical studies of cartilage as a treatment for cancer have been conducted since the early 1970s, relatively few results have been reported in the peer-reviewed scientific literature. None of the reported data have been from phase III clinical trials, and the results that have been reported are inconclusive. Additional clinical studies are now under way. At present, the use of cartilage (bovine [cow] or shark) as a treatment for 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 Cancer Complementary and Alternative Medicine ².

Changes to This Summary (04/17/2008)

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.

More Information

Additional Information about CAM Therapies

• The National Center for Complementary and Alternative Medicine ¹⁸ (NCCAM).
• The National Cancer Institute Office of Cancer Complementary and Alternative Medicine ¹⁹ (OCCAM).
• CAM on PubMed ²⁰, a special subset of the PubMed scientific literature database created through a partnership between NCCAM and the National Library of Medicine.

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ²¹

  Full description of the NCI PDQ database.

Other PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ²²

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ²³

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care ²⁴

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ²⁵

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ²⁶

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ²⁷

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ²⁸

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Glossary Terms

Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs.

A disorder of the skin in which oil glands and hair glands become inflamed.

Cancer that begins in cells that line certain internal organs and that have gland-like (secretory) properties.

The arrangement of amino acids in a protein. Proteins can be made from 20 different kinds of amino acids, and the structure and function of each protein are determined by the kinds of amino acids used to make it and how they are arranged.

Having to do with the anus. The anus is the opening of the rectum (last part of the large intestine) to the outside of the body.

Blood vessel formation. Tumor angiogenesis is the growth of new blood vessels needed for tumors to grow. This is caused by the release of chemicals by the tumor.

A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of new blood vessels needed for tumors to grow.

Having to do with reducing inflammation.

Having to do with reducing the growth of new blood vessels.

A type of protein made by plasma cells (a type of white blood cell) in response to an antigen (foreign substance). Each antibody can bind to only one specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen.

Having to do with stopping abnormal cell growth.

A type of cell death in which a series of molecular steps in a cell leads to its death. This is the body’s normal way of getting rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death.

Having to do with water.

A disease that causes inflammation and pain in the joints.

A tumor that begins in the brain or spinal cord in small, star-shaped cells called astrocytes.

A white blood cell that comes from bone marrow. As part of the immune system, B cells make antibodies and help fight infections. Also called B lymphocyte.

A type of skin cancer that arises from the basal cells, small round cells found in the lower part (or base) of the epidermis, the outer layer of the skin.

A substance that makes a loose mixture stick together. For example, binding agents can be used to make solid pills from loose powders.

The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body.

A tube through which the blood circulates in the body. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins.

Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.

Cancer that forms in tissues of the breast, usually the ducts (tubes that carry milk to the nipple) and lobules (glands that make milk). It occurs in both men and women, although male breast cancer is rare.

A mineral found in teeth, bones, and other body tissues.

A term for diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord.

Cancer that begins in the skin or in tissues that line or cover internal organs.

A tough, flexible tissue that lines joints and gives structure to the nose, ears, larynx, and other parts of the body.

A group or series of case reports involving patients who were given similar treatment. Reports of case series usually contain detailed information about the individual patients. This includes demographic information (for example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and follow-up after treatment.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

The lower, narrow end of the uterus that forms a canal between the uterus and vagina.

Treatment with drugs that kill cancer cells.

Cartilage cell. Chondrocytes make the structural components of cartilage.

The major glycosaminoglycan (a type of sugar molecule) in cartilage.

The membrane in hens' eggs that helps chicken embryos get enough oxygen and calcium for development. The calcium comes from the egg shell.

The system that contains the heart and the blood vessels and moves blood throughout the body. This system helps tissues get enough oxygen and nutrients, and it helps them get rid of waste products. The lymph system, which connects with the blood system, is often considered part of the circulatory system.

A drug used to treat many types of cancer. Cisplatin contains the metal platinum. It kills cancer cells by damaging their DNA and stopping them from dividing. Cisplatin is a type of alkylating agent.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical trial.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

A fibrous protein found in cartilage and other connective tissue.

A type of enzyme that breaks down the protein collagen.

The longest part of the large intestine, which is a tube-like organ connected to the small intestine at one end and the anus at the other. The colon removes water and some nutrients and electrolytes from partially digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus.

Cancer that forms in the tissues of the colon (the longest part of the large intestine). Most colon cancers are adenocarcinomas (cancers that begin in cells that make and release mucus and other fluids).

Cancer that develops in the colon (the longest part of the large intestine) and/or the rectum (the last several inches of the large intestine before the anus).

Forms of treatment that are used in addition to (complementary) or instead of (alternative) standard treatments. These practices generally are not considered standard medical approaches. Standard treatments go through a long and careful research process to prove they are safe and effective, but less is known about most types of CAM. CAM may include dietary supplements, megadose vitamins, herbal preparations, special teas, acupuncture, massage therapy, magnet therapy, spiritual healing, and meditation. Also called CAM.

The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission.

A membrane that lines the inner surface of the eyelid and also covers the front part of the eye. Conjunctivitis is inflammation of the conjunctiva.

In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works.

A currently accepted and widely used treatment for a certain type of disease, based on the results of past research. Also called conventional treatment.

The transparent part of the eye that covers the iris and the pupil and allows light to enter the inside.

Cells of a single type (human, animal, or plant) that have been adapted to grow continuously in the laboratory and are used in research.

Cell-killing.

A type of white blood cell that can directly destroy specific cells. T cells can be separated from other blood cells, grown in the laboratory, and then given to a patient to destroy tumor cells. Certain cytokines can also be given to a patient to help form cytotoxic T cells in the patient's body.

Inflammation of the skin.

The length of a straight line that extends from one edge of a tumor or other object, through its center and to the opposite edge. It is usually used to measure the size of round or spherical shapes.

A product that is added to the diet. A dietary supplement is taken by mouth, and usually contains one or more dietary ingredient (such as vitamin, mineral, herb, amino acid, and enzyme). Also called nutritional supplement.

The amount of medicine taken, or radiation given, at one time.

A bad taste in the mouth. Also called parageusia.

Upset stomach.

Swelling caused by excess fluid in body tissues.

Effectiveness. In medicine, the ability of an intervention (for example, a drug or surgery) to produce the desired beneficial effect.

Early stage in the development of a plant or an animal. In vertebrate animals (have a backbone or spinal column), this stage lasts from shortly after fertilization until all major body parts appear. In particular, in humans, this stage lasts from about 2 weeks after fertilization until the end of the seventh or eighth week of pregnancy.

The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart.

In clinical trials, an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.

The injection of a liquid through the anus into the large bowel.

A protein that speeds up chemical reactions in the body.

Patients whose response to a treatment can be measured because enough information has been collected.

A condition marked by extreme tiredness and inability to function due lack of energy. Fatigue may be acute or chronic.

An inactive substance used to make a product bigger or easier to handle. For example, fillers are often used to make pills or capsules because the amount of active drug is too small to be handled conveniently.

A type of glioma (cancer of the brain that comes from glial, or supportive, cells).

A type of long, unbranched polysaccharide molecule. Glycosaminoglycans are major structural components of cartilage and are also found in the cornea of the eye.

A type of white blood cell that helps stimulate immune system reactions. Helper T cells help activate cytotoxic T cells and macrophages by secreting cytokines. They also stimulate B cells to make antibodies.

An enlarged or swollen blood vessel, usually located near the anus or the rectum.

Disease of the liver causing inflammation. Symptoms include an enlarged liver, fever, nausea, vomiting, abdominal pain, and dark urine.

Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body’s natural hormones. Sometimes surgery is needed to remove the gland that makes a certain hormone. Also called endocrine therapy, hormone therapy, and hormone treatment.

Higher than normal levels of calcium in the blood. Some types of cancer increase the risk of hypercalcemia.

Higher than normal amount of glucose (a type of sugar) in the blood. Hyperglycemia can be a sign of diabetes or other conditions. Also called high blood sugar.

Abnormally low blood pressure.

A tentative proposal made to explain certain observations or facts that requires further investigation to be verified.

The complex group of organs and cells that defends the body against infections and other diseases.

In the laboratory (outside the body). The opposite of in vivo (in the body).

In the body. The opposite of in vitro (outside the body or in the laboratory).

Redness, swelling, pain, and/or a feeling of heat in an area of the body. This is a protective reaction to injury, disease, or irritation of the tissues.

Use of a syringe and needle to push fluids or drugs into the body; often called a "shot."

Within the peritoneal cavity (the area that contains the abdominal organs). Also called IP.

Into or within a vein. Intravenous usually refers to a way of giving a drug or other substance through a needle or tube inserted into a vein. Also called I.V..

In clinical trials, refers to a drug (including a new drug, dose, combination, or route of administration) or procedure that has undergone basic laboratory testing and received approval from the U.S. Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered investigational in other diseases or conditions. Also called experimental.

A researcher in a clinical trial or clinical study.

A glycosaminoglycan (a type of polysaccharide) found in cartilage and in the cornea of the eye.

Research done in a laboratory. These studies may use test tubes or animals to find out if a drug, procedure, or treatment is likely to be useful. Laboratory studies take place before any testing is done in humans.

A ranking system used to describe the strength of the results measured in a clinical trial or research study. The design of the study (such as a case report for an individual patient or a randomized double-blinded controlled clinical trial) and the endpoints measured (such as survival or quality of life) affect the strength of the evidence.

One of a pair of organs in the chest that supplies the body with oxygen, and removes carbon dioxide from the body.

Cancer that has spread from the original (primary) tumor to the lung.

A type of white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infections and other diseases.

A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells.

Cancerous. Malignant tumors can invade and destroy nearby tissue and spread to other parts of the body.

Having to do with the breast.

A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues (i.e., extracellular matrix proteins). Because these enzymes need zinc or calcium atoms to work properly, they are called metalloproteinases. Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis.

A form of cancer that begins in melanocytes (cells that make the pigment melanin). It may begin in a mole (skin melanoma), but can also begin in other pigmented tissues, such as in the eye or in the intestines.

The peritoneal membrane that attaches the intestines to the abdominal wall near the back.

The spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.” The metastatic tumor contains cells that are like those in the original (primary) tumor. The plural form of metastasis is metastases (meh-TAS-tuh-SEEZ).

Having to do with metastasis, which is the spread of cancer from one part of the body to another.

A measure of weight. A milligram is approximately 450,000 times smaller than a pound and 28,000 times smaller than an ounce.

A measure of volume for a liquid. A milliliter is approximately 950 times smaller than a quart and 30 times smaller than a fluid ounce. A milliliter of liquid and a cubic centimeter (cc) of liquid are the same.

A measure of length in the metric system. A millimeter is one thousandth of a meter. There are 25 millimeters in an inch.

The sum of the atomic masses of all atoms in a molecule, based on a scale in which the atomic masses of hydrogen, carbon, nitrogen, and oxygen are 1, 12, 14, and 16, respectively. For example, the molecular mass of water, which has two atoms of hydrogen and one atom of oxygen, is 18 (i.e., 2 + 16).

The smallest particle of a substance that has all of the physical and chemical properties of that substance. Molecules are made up of one or more atoms. If they contain more than one atom, the atoms can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms.

A type of cancer that begins in plasma cells (white blood cells that produce antibodies). Also called Kahler disease, myelomatosis, and plasma cell myeloma.

Cancer that arises in plasma cells, a type of white blood cell.

The National Cancer Institute, part of the National Institutes of Health of the United States Department of Health and Human Services, is the Federal Government's principal agency for cancer research. The National Cancer Institute conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the National Cancer Institute Web site at http://www.cancer.gov. Also called NCI.

A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer.

A clinical study that includes some, but not all, of the eligible patients identified by the researchers during the study registration period. This type of study does not usually have a control group.

Not cancerous.

By or having to do with the mouth.

A condition that is marked by a decrease in bone mass and density, causing bones to become fragile.

One of a pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus.

A glandular organ located in the abdomen. It makes pancreatic juices, which contain enzymes that aid in digestion, and it produces several hormones, including insulin. The pancreas is surrounded by the stomach, intestines, and other organs.

A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Also called partial remission.

PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, complementary and alternative medicine, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information, and more specific information about PDQ, can be found on the NCI's Web site at http://www.cancer.gov/cancertopics/pdq. Also called Physician Data Query.

A trial to study the safety, dosage levels, and response to a new treatment.

A study to test whether a new treatment has an anticancer effect (for example, whether it shrinks a tumor or improves blood test results) and whether it works against a certain type of cancer.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

A large carbohydrate molecule. It contains many small sugar molecules that are joined chemically. Also called glycan.

Research using animals to find out if a drug, procedure, or treatment is likely to be useful. Preclinical studies take place before any testing in humans is done.

The original tumor.

Cancer that is growing, spreading, or getting worse.

In medicine, a study or clinical trial in which participants are identified and then followed forward in time.

Cancer that forms in tissues of the prostate (a gland in the male reproductive system found below the bladder and in front of the rectum). Prostate cancer usually occurs in older men.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A molecule that contains both protein and glycosaminoglycans, which are a type of polysaccharide. Proteoglycans are found in cartilage and other connective tissues.

A chronic disease of the skin marked by red patches covered with white scales.

The overall enjoyment of life. Many clinical trials assess the effects of cancer and its treatment on the quality of life. These studies measure aspects of an individual’s sense of well-being and ability to carry out various activities.

The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called irradiation and radiotherapy.

Cancer that has recurred (come back), usually after a period of time during which the cancer could not be detected. The cancer may come back to the same place as the original (primary) tumor or to another place in the body. Also called recurrence.

Cancer that does not respond to treatment. The cancer may be resistant at the beginning of treatment or it may become resistant during treatment. Also called resistant cancer.

Chronic inflammation of the gastrointestinal tract, most commonly the small intestine and colon. Regional enteritis increases the risk for colorectal cancer and small intestine cancer. Also called Crohn disease.

A decrease in the size of a tumor or in the extent of cancer in the body.

The return of signs and symptoms of cancer after a period of improvement.

The most common type of kidney cancer. It begins in the lining of the renal tubules in the kidney. The renal tubules filter the blood and produce urine. Also called hypernephroma.

In medicine, an improvement related to treatment.

Looking back at events that have already taken place.

A cancer of the bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.

A person who has studied science, especially one who is active in a particular field of investigation.

A chronic disorder marked by hardening and thickening of the skin. Scleroderma can be localized or it can affect the entire body (systemic).

In males, the external sac that contains the testicles.

A problem that occurs when treatment affects healthy tissues or organs. Some common side effects of cancer treatment are fatigue, pain, nausea, vomiting, decreased blood cell counts, hair loss, and mouth sores.

The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage.

An abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancerous), or malignant (cancerous). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors.

Cancer that begins in squamous cells, which are thin, flat cells that look like fish scales. Squamous cells are found in the tissue that forms the surface of the skin, the lining of the hollow organs of the body, and the passages of the respiratory and digestive tracts. Also called epidermoid carcinoma.

Cancer that is neither decreasing nor increasing in extent or severity.

The extent of a cancer in the body. Staging is usually based on the size of the tumor, whether lymph nodes contain cancer, and whether the cancer has spread from the original site to other parts of the body.

Stage III is divided into stages IIIA and IIIB. In stage IIIA, cancer has spread to lymph nodes on the same side of the chest as the tumor; the tumor may be any size and cancer may have spread to the main bronchus, the chest wall, the diaphragm, the pleura around the lungs, or the membrane around the heart, but cancer has not spread to the trachea; and part or all of the lung may have collapsed or developed pneumonitis (inflammation of the lung). In stage IIIB, the tumor may be any size and has spread to lymph nodes above the collarbone or in the opposite side of the chest from the tumor; AND/OR to any of the following places: the heart, major blood vessels that lead to or from the heart, the chest wall, the diaphragm, the trachea, the esophagus, the sternum (chest bone) or backbone, to more than one place in the same lobe of the lung, and/or into the fluid of the pleural cavity surrounding the lung.

Beneath the skin.

A procedure to remove or repair a part of the body or to find out whether disease is present. An operation.

One type of white blood cell that attacks virus-infected cells, foreign cells, and cancer cells. T cells also produce a number of substances that regulate the immune response. Also called T lymphocyte.

One of two egg-shaped glands inside the scrotum that produce sperm and male hormones. Also called testicle.

Having to do with treating disease and helping healing take place.

On the surface of the body.

Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects.

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancerous), or malignant (cancerous). Also called neoplasm.

Chronic inflammation of the colon that produces ulcers in its lining. This condition is marked by abdominal pain, cramps, and loose discharges of pus, blood, and mucus from the bowel.

A substance made by cells that stimulates new blood vessel formation. Also called VEGF.

Refers to a blood cell that does not contain hemoglobin. White blood cells include lymphocytes, neutrophils, eosinophils, macrophages, and mast cells. These cells are made by bone marrow and help the body fight infections and other diseases. Also called WBC.

A break in the skin or other body tissues caused by injury or surgical incision (cut).