Cartilage (Bovine and Shark) 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 1 study, cells from 22 freshly isolated human tumors (9 ovary, 3 lung, 2 brain, 2 breast, and 1 each of sarcoma, melanoma, colon, pancreas, cervix, and testis) and 3 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 3 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 to 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 “toxic” 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. (See Human/Clinical Studies for a discussion of human studies of Catrix.) 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] However, 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] It is important to note, however, that the shark cartilage product tested in this study was examined at only 1 concentration (0.75 mg/mL).[2] The immune-system–stimulating potential of cartilage has also been investigated in laboratory and animal studies, but just 1 study has been reported in the peer-reviewed, scientific literature.[9] In that 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 given by intraperitoneal or intravenous injection. It was not observed when oral formulations of Catrix were used.[9] It is important to note that, 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 to 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 in a peer-reviewed, scientific journal. To date, no studies of the immune-system–stimulating potential of shark cartilage have been reported. A large number of laboratory and animal studies have been published concerning the antiangiogenic potential of cartilage.[2,10-25,8,26] Overall, these studies have revealed the presence of at least 3 angiogenesis inhibitors in bovine cartilage [11,12,15,16,19,21] Reviewed in [14,27] and at least 2 in shark cartilage.[2,24,25] Three angiogenesis inhibitors in bovine cartilage have been very well characterized.[11,12,15,16,19,21] Reviewed in [14,27] They are relatively small proteins with molecular masses that range from 23,000 to 28,000.[11,12,21] Reviewed in [14] These proteins, called cartilage-derived inhibitor (CDI), cartilage-derived antitumor factor (CATF), and cartilage-derived collagenase inhibitor (CDCI) by the researchers who purified them,[11,12,19] have been shown to block endothelial cell proliferation in vitro and new blood vessel formation in the chorioallantoic membrane of chicken embryos.[12,15,16,19,21] Reviewed in [14,27] Two of the proteins (CDI and CDCI) have been shown to inhibit matrix metalloproteinase activity in vitro,[11,12,16] Reviewed in [14] and 1 (CDI) has been shown to inhibit endothelial cell migration in vitro.[12] Reviewed in [14] These proteins do not block the proliferation of normal cells or of tumor cells in vitro.[12,15,19] Reviewed in [14,27] 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 TIMP-1 (tissue inhibitor of matrix metalloproteinases 1), ChMI (chondromodulin I), and TIMP-2 (tissue inhibitor of matrix metalloproteinases 2), respectively.[11,12,16,21] Reviewed in [27] 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.[13] This inhibitor, which has been named chondrocyte-derived inhibitor (ChDI), is a protein that has a molecular mass of approximately 36,000.[13] It has been reported that ChDI and CDI/TIMP-1 have similar antiangiogenic activities,[13] Reviewed in [14,27] 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 1 type of angiogenesis inhibitor. One shark cartilage inhibitor, named U-995, reportedly contains 2 small proteins, 1 with a molecular mass of approximately 14,000 and the other with a molecular mass of approximately 10,000.[24] Both proteins have shown antiangiogenic activity when tested individually.[24] The exact relationship between these 2 proteins, as well as 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, and matrix metalloproteinase activity in vitro and the formation of new blood vessels in the chorioallantoic membrane of chicken embryos.[24] It does not appear to inhibit the proliferation of other types of normal cells or of cancer cells in vitro.[24] 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.[24] The second angiogenesis inhibitor identified in shark cartilage appears to have been studied independently by 3 groups of investigators.[2,25,28] This inhibitor, which was named SCF2 by 1 of the groups,[28] is a proteoglycan that has a molecular mass of less than 10,000. Proteoglycans are combinations of glycosaminoglycans and protein. Reviewed in [29] The principal glycosaminoglycan in SCF2 is keratan sulfate.[28] SCF2 has been shown to block endothelial cell proliferation in vitro,[2,25,28] the formation of new blood vessels in the chorioallantoic membrane of chicken embryos,[2,25] and tumor-induced angiogenesis in the cornea of rabbits.[2,25] Other studies have demonstrated that AE-941/Neovastat, the previously mentioned aqueous extract of shark cartilage, has antiangiogenic activity,[8,10,26] Reviewed in [7] 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.[8,10,30] 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.[31] Reviewed in [7] It also appears to inhibit the action of vascular endothelial growth factor (VEGF), thus interfering with the communication between tumor cells and nearby blood vessels.[26] Reviewed in [7] 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 [5,7,32] In the Lewis lung carcinoma experiments, AE-941/Neovastat enhanced the antimetastatic effect of the chemotherapy drug cisplatin.[8] Reviewed in [5,7,32] Additional in vivo studies of the antitumor potential of shark cartilage have been published in the peer-reviewed, scientific literature.[23,33,34] In 1 study, oral administration of powdered shark cartilage (no brand name given) was shown to inhibit chemically induced angiogenesis in the mesenteric membrane of rats.[23] 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.[33] In contrast, it was reported in a third study that oral administration of 2 powdered shark cartilage products, Sharkilage and MIA Shark Powder, did not inhibit the growth or the metastasis of SCCVII squamous cell carcinomas in mice.[34] References 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] 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] 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] AE 941--Neovastat. Drugs R D 1 (2): 135-6, 1999. [PUBMED Abstract] Reviews of Therapies: Biologic/Organic/Pharmacologic Therapies: Cartilage. Houston, Tex: M.D. Anderson Cancer Center, 2003. Available online. Last accessed June 11, 2004. 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] 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] Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of catrix. J Biol Response Mod 7 (5): 498-512, 1988. [PUBMED Abstract] 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] 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] 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] 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] 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] 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] 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] Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Adv Exp Med Biol 476: 209-23, 2000. [PUBMED Abstract] Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994. 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] 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] Wojtowicz-Praga S: Clinical potential of matrix metalloprotease inhibitors. Drugs R D 1 (2): 117-29, 1999. [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] 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] Read More On This Subject

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