Table of Contents Purpose of This PDQ Summary Overview General Information History Laboratory/Animal/Preclinical Studies Human/Clinical Studies Adverse Effects Overall Level of Evidence for Cartilage Changes to This Summary (04/17/2008) More Information
Purpose of This PDQ Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of cartilage as a treatment for cancer. The summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board 1.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level of evidence designation. These designations are intended to help the readers assess the strength of the evidence supporting the use of specific interventions or treatment strategies. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system 2 in developing its level of evidence designations. These designations should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version 3, which is written in less technical language. Overview
This complementary
and alternative medicine (CAM) information summary provides an overview of
the use of cartilage as a treatment
for cancer. The summary includes a brief history of cartilage research, the
results of clinical studies, and
possible side effects of cartilage use.
This summary contains the following key information:
- Bovine (cow) cartilage and shark cartilage have been studied as
treatments for cancer and other medical conditions for more than 30
years.
- Numerous cartilage products are sold commercially in the United States
as dietary supplements.
- Three principal mechanisms of action have been proposed to explain the antitumor potential of cartilage: 1) it kills cancer cells directly; 2) it
stimulates the immune system; and 3) it blocks the formation of new blood vessels (angiogenesis), which tumors need
for unrestricted growth.
- At least three different inhibitors of angiogenesis have been identified
in bovine cartilage, and two angiogenesis inhibitors have been purified from shark cartilage.
- Few human studies of cartilage as a treatment for cancer have been reported to date, and the results
are inconclusive.
- Additional clinical trials of cartilage as a treatment for cancer are now being conducted.
Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Web site Dictionary 4, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window. All linked terms and their corresponding definitions will appear in a glossary in the printable version of the summary.
Reference citations in some PDQ CAM information summaries may include links to external Web sites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute (NCI). General Information
Bovine (cow) cartilage and shark cartilage have been investigated as treatments
for cancer, psoriasis, arthritis, and a number of other medical
conditions for more than 30 years.[1-13] Reviewed in [14-20] At least some of
the interest in cartilage as a treatment for cancer arose from the mistaken
belief that sharks, whose skeletons are
made primarily of cartilage, are not affected by this disease. Reviewed in
[16,21,22] Although reports of malignant tumors in sharks are rare, a variety of cancers have been detected in these
animals. Reviewed in [21-24] Nonetheless, several substances that have
antitumor activity have been identified in cartilage.[25-47] Reviewed in
[2-4,7,15-20,46,48-50] More than half a dozen clinical studies of cartilage as a
treatment for cancer have already been conducted,[2-4,7-9,50,51] Reviewed in
[6,15-19] and additional clinical studies (MDA-ID-99303 5 and AETERNA-AE-MM-00-02 6) are now under way. Reviewed
in [6,15,51]
The absence of blood vessels in cartilage led to the hypothesis that cartilage cells (also
known as chondrocytes) produce one
or more substances that inhibit blood vessel formation. Reviewed in
[28-31,36,37,49] The formation of new blood vessels or angiogenesis is
necessary for tumors to grow larger than a few millimeters in diameter (i.e., larger than approximately
100,000 to 1,000,000 cells) because tumors, like normal tissues, must obtain
most of their oxygen and nutrients from blood. Reviewed in [34,35,42,52-55] A
developing tumor, therefore, cannot continue to grow unless it establishes
connections to the circulatory
system of its host. It has been reported that tumors can initiate the
process of angiogenesis when they contain as few as 100 cells.[54] Inhibition
of angiogenesis at this early stage may,
in some instances, lead to complete tumor regression.[54] The possibility that
cartilage could be a source of one or more types of angiogenesis inhibitors for the treatment of cancer has prompted much research.
The major structural components of cartilage include several types of the protein collagen and several types of glycosaminoglycans, which are polysaccharides. Reviewed in
[20,30,31,40,49,55,56] Chondroitin sulfate is the
major glycosaminoglycan in cartilage. Reviewed in [40,55] Although there is no
evidence that the collagens in cartilage, or their breakdown products, can
inhibit angiogenesis, there is evidence that shark cartilage contains at least
one angiogenesis inhibitor that has a glycosaminoglycan component (refer to the Laboratory/Animal/Preclinical Studies 7 section of this summary for more information).[47] Other data indicate that
most of the antiangiogenic activity in cartilage is not associated with the major structural components.
Reviewed in [27,31,49]
Some glycosaminoglycans in cartilage reportedly have anti-inflammatory and immune-system –stimulating properties,[57,58] Reviewed in [1,2,14,16] and it has been
suggested that either they or some of their breakdown products are toxic to
tumor cells.[25] Reviewed in [2,3] Thus, the antitumor potential of cartilage
may involve more than one mechanism of action.
Cartilage products are sold commercially in the United States as dietary
supplements. More than 40 different brand names of shark cartilage alone are
available to consumers. Reviewed in [18] In the United States, dietary
supplements are regulated as foods, not drugs. Therefore, premarket
evaluation and approval by the U.S. Food and Drug Administration (FDA) are not
required unless specific disease prevention or treatment claims are made.
Because manufacturers of cartilage products are not required to show evidence
of anticancer or other biologic effects, Reviewed in [18] it is unclear whether
any of these products has therapeutic potential. In addition,
individual products may vary considerably from lot to lot because standard
manufacturing processes do not exist, and binding agents and fillers may be added during
production. Reviewed in [18] The FDA has not approved the use of cartilage as a treatment for cancer or any other medical condition. The FDA is notifying consumers of a refund program for purchasers of Lane Labs-USA, Inc.'s, BeneFin, its shark cartilage product. Consumers are eligible for a partial refund of the purchase price and any shipping and handling costs if this product was purchased between September 22, 1999 and July 12, 2004.
To conduct clinical drug research in the United States, researchers must
file an Investigational New Drug (IND) application with the FDA. To date, IND
status has been granted to at least four groups of investigators, one of which is the MDA-ID-99303 trial, to study
cartilage as a treatment for cancer. [7,59] Reviewed in [19] Because the
IND application process is confidential and because the existence of an IND
can be disclosed only by the applicants, it is not known whether other
applications have been made.
In animal studies, cartilage products have been administered in a variety
of ways. In some studies, oral administration of either liquid or powdered forms has been
used.[20,40,41,44,45,60] Reviewed in [15,48] In other studies, cartilage
products have been given by injection (intravenous or intraperitoneal), applied topically, or placed in slow-release
plastic pellets that were surgically implanted.[27,28,33,34,36,39,41,43,45]
Reviewed in [29,47,49] Most of the latter studies investigated the effects of
cartilage products on the development of blood vessels in the chorioallantoic membrane of chicken embryos, the cornea of rabbits, or the conjunctiva of
mice.[27,28,33,36,39,41,43,45] Reviewed in [29,47,49]
In human studies (MDA-ID-99303, AETERNA-AE-MM-00-02, and NCCTG-971151 8), cartilage products have been administered topically or
orally, or they have been given by enema or subcutaneous injection.[2-4,7-9] Reviewed in AETERNA-AE-RC-99-02 9,[6,15-17,19,61] For oral
administration, liquid, powdered, and pill forms have been
used as described in MDA-ID-99303, NCCTG-971151, and AETERNA-AE-MM-00-02.[2-4,7-9] Reviewed in [6,15-17,19] The dose and duration of
cartilage treatment have varied in human studies, in part because different
types of products have been tested.
In this summary, the brand name (i.e., registered or trademarked name) of
the cartilage product(s) used in individual studies will be identified
wherever possible.
References
-
Prudden JF, Balassa LL: The biological activity of bovine cartilage preparations. Clinical demonstration of their potent anti-inflammatory capacity with supplementary notes on certain relevant fundamental supportive studies. Semin Arthritis Rheum 3 (4): 287-321, 1974 Summer.
[PUBMED Abstract]
-
Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
[PUBMED Abstract]
-
Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985.
[PUBMED Abstract]
-
Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994.
-
Dupont E, Savard PE, Jourdain C, et al.: Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis. J Cutan Med Surg 2 (3): 146-52, 1998.
[PUBMED Abstract]
-
Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001.
[PUBMED Abstract]
-
Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998.
[PUBMED Abstract]
-
Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998.
-
Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-554, 1999.
-
Iandoli R: Shark cartilage in the treatment of psoriasis. Dermatologia Clinica 21 (part 1): 39-42, 2001.
-
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.
-
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.
-
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.
-
Prudden JF, Migel P, Hanson P, et al.: The discovery of a potent pure chemical wound-healing accelerator. Am J Surg 119 (5): 560-4, 1970.
[PUBMED Abstract]
-
AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.
[PUBMED Abstract]
-
Cassileth BR: Shark and bovine cartilage therapies. In: Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. New York, NY: WW Norton & Company, 1998, pp 197-200.
-
Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. 11 Last accessed October 30, 2008.
-
Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1: 414-16, 1995.
-
Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.
[PUBMED Abstract]
-
Fontenele JB, Araújo GB, de Alencar JW, et al.: The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent. Biol Pharm Bull 20 (11): 1151-4, 1997.
[PUBMED Abstract]
-
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]
-
Finkelstein JB: Sharks do get cancer: few surprises in cartilage research. J Natl Cancer Inst 97 (21): 1562-3, 2005.
[PUBMED Abstract]
-
Schlumberger HG, Lucke B: Tumors of fishes, amphibians, and reptiles. Cancer Res 8: 657-754, 1948.
-
Wellings SR: Neoplasia and primitive vertebrate phylogeny: echinoderms, prevertebrates, and fishes--A review. Natl Cancer Inst Monogr 31: 59-128, 1969.
[PUBMED Abstract]
-
Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. J Biol Response Mod 4 (6): 590-5, 1985.
[PUBMED Abstract]
-
Murray JB, Allison K, Sudhalter J, et al.: Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. J Biol Chem 261 (9): 4154-9, 1986.
[PUBMED Abstract]
-
Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990.
[PUBMED Abstract]
-
Moses MA, Sudhalter J, Langer R: Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes. J Cell Biol 119 (2): 475-82, 1992.
[PUBMED Abstract]
-
Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr.
[PUBMED Abstract]
-
Takigawa M, Pan HO, Enomoto M, et al.: A clonal human chondrosarcoma cell line produces an anti-angiogenic antitumor factor. Anticancer Res 10 (2A): 311-5, 1990 Mar-Apr.
[PUBMED Abstract]
-
Ohba Y, Goto Y, Kimura Y, et al.: Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochim Biophys Acta 1245 (1): 1-8, 1995.
[PUBMED Abstract]
-
Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977.
[PUBMED Abstract]
-
Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976.
[PUBMED Abstract]
-
Langer R, Conn H, Vacanti J, et al.: Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc Natl Acad Sci U S A 77 (7): 4331-5, 1980.
[PUBMED Abstract]
-
Takigawa M, Shirai E, Enomoto M, et al.: Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation of endothelial cells in culture. Cell Biol Int Rep 9 (7): 619-25, 1985.
[PUBMED Abstract]
-
Takigawa M, Shirai E, Enomoto M, et al.: A factor in conditioned medium of rabbit costal chondrocytes inhibits the proliferation of cultured endothelial cells and angiogenesis induced by B16 melanoma: its relation with cartilage-derived anti-tumor factor (CATF). Biochem Int 14 (2): 357-63, 1987.
[PUBMED Abstract]
-
Hiraki Y, Inoue H, Iyama K, et al.: Identification of chondromodulin I as a novel endothelial cell growth inhibitor. Purification and its localization in the avascular zone of epiphyseal cartilage. J Biol Chem 272 (51): 32419-26, 1997.
[PUBMED Abstract]
-
Pauli BU, Memoli VA, Kuettner KE: Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. J Natl Cancer Inst 67 (1): 65-73, 1981.
[PUBMED Abstract]
-
Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.
[PUBMED Abstract]
-
Davis PF, He Y, Furneaux RH, et al.: Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvasc Res 54 (2): 178-82, 1997.
[PUBMED Abstract]
-
Sheu JR, Fu CC, Tsai ML, et al.: Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities. Anticancer Res 18 (6A): 4435-41, 1998 Nov-Dec.
[PUBMED Abstract]
-
McGuire TR, Kazakoff PW, Hoie EB, et al.: Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium. Pharmacotherapy 16 (2): 237-44, 1996 Mar-Apr.
[PUBMED Abstract]
-
Oikawa T, Ashino-Fuse H, Shimamura M, et al.: A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett 51 (3): 181-6, 1990.
[PUBMED Abstract]
-
Morris GM, Coderre JA, Micca PL, et al.: Boron neutron capture therapy of the rat 9L gliosarcoma: evaluation of the effects of shark cartilage. Br J Radiol 73 (868): 429-34, 2000.
[PUBMED Abstract]
-
Dupont E, Falardeau P, Mousa SA, et al.: Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue. Clin Exp Metastasis 19 (2): 145-53, 2002.
[PUBMED Abstract]
-
Béliveau R, Gingras D, Kruger EA, et al.: The antiangiogenic agent neovastat (AE-941) inhibits vascular endothelial growth factor-mediated biological effects. Clin Cancer Res 8 (4): 1242-50, 2002.
[PUBMED Abstract]
-
Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.
[PUBMED Abstract]
-
Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.
[PUBMED Abstract]
-
Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999.
[PUBMED Abstract]
-
Batist G, Champagne P, Hariton C, et al.: Dose-survival relationship in a phase II study of Neovastat in refractory renal cell carcinoma patients. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1907, 2002.
-
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]
-
Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992.
[PUBMED Abstract]
-
Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994.
[PUBMED Abstract]
-
Li CY, Shan S, Huang Q, et al.: Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92 (2): 143-7, 2000.
[PUBMED Abstract]
-
Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
-
Cremer MA, Rosloniec EF, Kang AH: The cartilage collagens: a review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease. J Mol Med 76 (3-4): 275-88, 1998.
[PUBMED Abstract]
-
Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.
[PUBMED Abstract]
-
Houck JC, Jacob RA, DeAngelo L, et al.: The inhibition of inflammation and the acceleration of tissue repair by cartilage powder. Surgery 51: 632-38, 1962.
-
Simone CB, Simone NL, Simone CB 2nd: Shark cartilage for cancer. Lancet 351 (9113): 1440, 1998.
[PUBMED Abstract]
-
Horsman MR, Alsner J, Overgaard J: The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma. Acta Oncol 37 (5): 441-5, 1998.
[PUBMED Abstract]
-
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
-
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.
-
Prudden JF, Balassa LL: The biological activity of bovine cartilage preparations. Clinical demonstration of their potent anti-inflammatory capacity with supplementary notes on certain relevant fundamental supportive studies. Semin Arthritis Rheum 3 (4): 287-321, 1974 Summer.
[PUBMED Abstract]
-
Prudden JF, Migel P, Hanson P, et al.: The discovery of a potent pure chemical wound-healing accelerator. Am J Surg 119 (5): 560-4, 1970.
[PUBMED Abstract]
-
Cassileth BR: Shark and bovine cartilage therapies. In: Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. New York, NY: WW Norton & Company, 1998, pp 197-200.
-
Fontenele JB, Araújo GB, de Alencar JW, et al.: The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent. Biol Pharm Bull 20 (11): 1151-4, 1997.
[PUBMED Abstract]
-
Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976.
[PUBMED Abstract]
-
Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
[PUBMED Abstract]
-
Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985.
[PUBMED Abstract]
-
Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. J Biol Response Mod 4 (6): 590-5, 1985.
[PUBMED Abstract]
-
Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.
[PUBMED Abstract]
-
Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.
[PUBMED Abstract]
-
Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998.
[PUBMED Abstract]
-
Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.
[PUBMED Abstract]
-
Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. 11 Last accessed October 30, 2008.
-
Folkman J: The role of angiogenesis in tumor growth. Semin Cancer Biol 3 (2): 65-71, 1992.
[PUBMED Abstract]
-
Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Ann N Y Acad Sci 732: 263-72, 1994.
[PUBMED Abstract]
-
Li CY, Shan S, Huang Q, et al.: Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J Natl Cancer Inst 92 (2): 143-7, 2000.
[PUBMED Abstract]
-
Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
-
Moses MA: The regulation of neovascularization of matrix metalloproteinases and their inhibitors. Stem Cells 15 (3): 180-9, 1997.
[PUBMED Abstract]
-
Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 103 (9): 1237-41, 1999.
[PUBMED Abstract]
-
Haas TL, Madri JA: Extracellular matrix-driven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc Med 9 (3-4): 70-7, 1999 Apr-May.
[PUBMED Abstract]
-
McCawley LJ, Matrisian LM: Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6 (4): 149-56, 2000.
[PUBMED Abstract]
-
Mandal M, Mandal A, Das S, et al.: Clinical implications of matrix metalloproteinases. Mol Cell Biochem 252 (1-2): 305-29, 2003.
[PUBMED Abstract]
-
Takigawa M, Pan HO, Enomoto M, et al.: A clonal human chondrosarcoma cell line produces an anti-angiogenic antitumor factor. Anticancer Res 10 (2A): 311-5, 1990 Mar-Apr.
[PUBMED Abstract]
-
Ohba Y, Goto Y, Kimura Y, et al.: Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochim Biophys Acta 1245 (1): 1-8, 1995.
[PUBMED Abstract]
-
Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surg Forum 28: 499-501, 1977.
[PUBMED Abstract]
-
Takigawa M, Shirai E, Enomoto M, et al.: Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation of endothelial cells in culture. Cell Biol Int Rep 9 (7): 619-25, 1985.
[PUBMED Abstract]
-
Takigawa M, Shirai E, Enomoto M, et al.: A factor in conditioned medium of rabbit costal chondrocytes inhibits the proliferation of cultured endothelial cells and angiogenesis induced by B16 melanoma: its relation with cartilage-derived anti-tumor factor (CATF). Biochem Int 14 (2): 357-63, 1987.
[PUBMED Abstract]
-
Pauli BU, Memoli VA, Kuettner KE: Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. J Natl Cancer Inst 67 (1): 65-73, 1981.
[PUBMED Abstract]
-
Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.
[PUBMED Abstract]
-
Suzuki F: Cartilage-derived growth factor and antitumor factor: past, present, and future studies. Biochem Biophys Res Commun 259 (1): 1-7, 1999.
[PUBMED Abstract]
-
Murray JB, Allison K, Sudhalter J, et al.: Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. J Biol Chem 261 (9): 4154-9, 1986.
[PUBMED Abstract]
-
Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.
[PUBMED Abstract]
-
Pettit GR, Ode RH: Antineoplastic agents L: isolation and characterization of sphyrnastatins 1 and 2 from the hammerhead shark Sphyrna lewini. J Pharm Sci 66 (5): 757-8, 1977.
[PUBMED Abstract]
-
Sigel MM, Fugmann RA: Studies on immunoglobulins reactive with tumor cells and antigens. Cancer Res 28 (7): 1457-9, 1968.
[PUBMED Abstract]
-
Snodgrass MJ, Burke JD, Meetz GD: Inhibitory effect of shark serum on the Lewis lung carcinoma. J Natl Cancer Inst 56 (5): 981-4, 1976.
[PUBMED Abstract]
-
Pugliese PT, Heinerman J: Devour Disease with Shark Liver Oil. Green Bay, Wis: Impakt Communications, 1999.
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
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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.
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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.
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Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
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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.
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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.
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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.
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Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988.
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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.
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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.
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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.
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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]
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Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248 (4961): 1408-10, 1990.
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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.
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Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol 11 (Suppl 8): S67-9, 1993 Mar-Apr.
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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.
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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.
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Langer R, Brem H, Falterman K, et al.: Isolations of a cartilage factor that inhibits tumor neovascularization. Science 193 (4247): 70-2, 1976.
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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]
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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]
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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]
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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]
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Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221 (4616): 1185-7, 1983.
[PUBMED Abstract]
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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]
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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]
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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]
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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]
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Cho J, Kim Y: Sharks: a potential source of antiangiogenic factors and tumor treatments. Mar Biotechnol (NY) 4 (6): 521-5, 2002.
[PUBMED Abstract]
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Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
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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]
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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]
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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]
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Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000.
[PUBMED Abstract]
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Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.
[PUBMED Abstract]
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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]
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Gingras D, Boivin D, Deckers C, et al.: Neovastat--a novel antiangiogenic drug for cancer therapy. Anticancer Drugs 14 (2): 91-6, 2003.
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Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.
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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.
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Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999.
[PUBMED Abstract]
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Dredge K: AE-941 (AEterna). Curr Opin Investig Drugs 5 (6): 668-77, 2004.
[PUBMED Abstract]
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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]
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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.
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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.
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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]
Cartilage Use in Cancer Treatment: Clinical Studies With Therapeutic Endpointsa,b
Reference Citation(s)
|
Type of Study
|
Type(s) of Cancer
|
Cartilage
Product (Source)
|
No. of Patients: Treated; Control
|
Strongest Benefit Reportedc
|
Concurrent Therapyd
|
Level
of Evidence Scoree
|
[1] |
Nonconsecutive case series
|
Various advanced or recurrent |
Catrix (bovine) |
31;
None |
Complete response, 19 patients |
Yes |
3iiiDiii |
[2] |
Phase II trial |
Various metastatic |
Catrix (bovine) |
9;
None |
Complete response, 1
patient, metastatic renal cell carcinoma |
No |
3iiiDiii |
[3] |
Phase II trial |
Metastatic renal cell |
Catrix (bovine) |
35;
None |
Partial response, 3 of
22 evaluable patients |
Unknown |
Nonef |
[10,17] |
Two phase I/II trialsg |
Various advanced, refractory solid tumors |
AE-941/ Neovastat (shark) |
331;
None |
Improved survival, higher versus lower
doses, patients with stage III/IV non-small cell lung cancer (unplanned retrospective analysis), and patients with refractory renal cell carcinoma (prospective analysis) |
Unknown |
Nonef |
[9] |
Phase I/II trial |
Advanced non-small cell lung cancer
|
AT-941/Neovastat (shark)
|
80; None
|
No dose-limiting toxicity found. Improved survival time in patients receiving the highest doses when survival analysis was conducted, and stable disease for greater number of patients receiving higher doses. No tumor response observed. |
Yes or refused standard therapy |
None |
[4] |
Phase I/II trial |
Various advanced solid tumors |
Cartilade (shark) |
60;
None |
Stable disease for 12 weeks or more, 10 of
50 evaluable patients |
No |
3iiiDiii |
[5] |
Phase II trial |
Metastatic, refractory breast |
Unknown (shark) |
20;
None |
Stable disease for 8 weeks or more, 2 of
10 evaluable patients |
No |
Nonef |
[5] |
Phase II trial |
Metastatic, hormone- refractory prostate |
Unknown (shark) |
12;
None |
Stable disease for 20 weeks or more, 3 of
10 evaluable patients |
No |
Nonef |
[6] |
Phase II trial |
Various advanced brain |
BeneFin (shark) |
12;
None |
Stable disease for 20 weeks or more, 2 of
10 evaluable patients |
No |
Nonef |
[8] |
Phase III randomized, placebo-controlled, double-blind trial (2 arms) |
Breast and colorectal |
BeneFin (shark) |
42; 41 |
No statistically significant difference |
No |
1i |
No. = number.
|
aSee text and glossary for additional information and definitions of most
terms.
|
bOther clinical studies have been conducted, but no results have been
reported.
|
cStrongest evidence reported that the treatment under study has
anticancer activity or otherwise improves the well-being of cancer patients.
|
dChemotherapy, radiation therapy, hormonal therapy, or cytokine therapy
given/allowed at the same time as cartilage therapy.
|
eFor information about Levels of Evidence analysis and an explanation of
the level of evidence scores, see Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine 2.
|
fStudy results reported in review article or abstract form only; insufficient information presented for Level of Evidence analysis.
|
gInsufficient information available to describe these studies separately.
|
References
-
Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
[PUBMED Abstract]
-
Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985.
[PUBMED Abstract]
-
Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994.
-
Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998.
[PUBMED Abstract]
-
Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998.
-
Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-554, 1999.
-
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.
-
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]
-
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]
-
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]
-
AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999.
[PUBMED Abstract]
-
Cassileth BR: Shark and bovine cartilage therapies. In: Cassileth BR, ed.: The Alternative Medicine Handbook: The Complete Reference Guide to Alternative and Complementary Therapies. New York, NY: WW Norton & Company, 1998, pp 197-200.
-
Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. 11 Last accessed October 30, 2008.
-
Holt S: Shark cartilage and nutriceutical update. Altern Complement Ther 1: 414-16, 1995.
-
Hunt TJ, Connelly JF: Shark cartilage for cancer treatment. Am J Health Syst Pharm 52 (16): 1756, 1760, 1995.
[PUBMED Abstract]
-
AE 941. Drugs R D 5 (2): 83-9, 2004.
[PUBMED Abstract]
-
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]
-
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]
-
Ryoo JJ, Cole CE, Anderson KC: Novel therapies for multiple myeloma. Blood Rev 16 (3): 167-74, 2002.
[PUBMED Abstract]
-
Bukowski RM: AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma. Expert Opin Investig Drugs 12 (8): 1403-11, 2003.
[PUBMED Abstract]
-
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
-
Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. J Biol Response Mod 4 (6): 551-84, 1985.
[PUBMED Abstract]
-
Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. J Biol Response Mod 4 (6): 585-9, 1985.
[PUBMED Abstract]
-
Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-769, 246, 1994.
-
Miller DR, Anderson GT, Stark JJ, et al.: Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 16 (11): 3649-55, 1998.
[PUBMED Abstract]
-
Leitner SP, Rothkopf MM, Haverstick L, et al.: Two phase II studies of oral dry shark cartilage powder (SCP) with either metastatic breast or prostate cancer refractory to standard treatment. [Abstract] Proceedings of the American Society of Clinical Oncology 17: A-240, 1998.
-
Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-554, 1999.
-
Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. 11 Last accessed October 30, 2008.
-
Jungi WF: Dangerous nutrition. Support Care Cancer 11 (4): 197-8, 2003.
[PUBMED Abstract]
-
Ashar B, Vargo E: Shark cartilage-induced hepatitis. Ann Intern Med 125 (9): 780-1, 1996.
[PUBMED Abstract]
-
Falardeau P, Champagne P, Poyet P, et al.: Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 28 (6): 620-5, 2001.
[PUBMED Abstract]
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
About PDQ
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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). |