-IBIS-1.7.6-
rx
nutritional supplement
Shark Cartilage and Bovine Cartilage
Nutrition
Definition
» overview:
Cartilage is a tough, elastic, translucent connective tissue found in humans and animals. Apart from the nose, ears, knees and other joints most cartilage converts into bone as an animal matures. Unlike cows and most other animals, sharks have no bones, only cartilage. Commercially available cartilage for supplemental use is derived from either sharks or cows (bovine).
Starting in 1954 with a study published by John Prudden and associates, researchers demonstrated that wound healing could be enhanced by inserting chips of bovine tracheal cartilage inserted into wounds. Subsequent research found that cartilage was particularly effective in reversing steroid-induced inhibition of wound healing. Subsequent research by Prudden and others on bovine cartilage and Lane and others on shark cartilage have focused on chronic inflammatory conditions and malignant tumors.
The primary clinical uses of cartilage include reducing inflammation, regulating and stimulating immune function, accelerating wound healing, providing nutrient support for joint repair, inhibiting growth and spread of tumors.
While some positive preliminary studies exist and anecdotal reports are widespread so are harsh criticisms denouncing cartilage as a useless and expensive fraud. Large scale, well-designed clinical research on the efficacy of cartilage for the treatment of cancer, arthritis or other conditions have not been conducted so no conclusive evidence is available.
» chemistry:
Cartilage is comprised of mucopolysaccharides, protein substances, calcium, sulfur, and collagen.
Chondroitin sulfate is the most well known of the glycosaminoglycans (GAGs) found in cartilage. It has been used for the treatment of arthritis and musculoskeletal injuries for decades, particularly in Europe.
For several decades researchers have reported that cartilage, especially from sharks, contains angiogenesis inhibitor proteins. This theory of preventing angiogenesis (formation of new blood vessels) was first proposed by Dr. Judah Folkman, of Harvard University, in 1971. Since cartilage is an avascular tissue, it has been hypothesized that there may be factors found in cartilage that inhibit blood vessel formation. A variety of test-tube experiments using chick embryos and animal-based research has shown that shark cartilage extracts prevent new blood vessels from forming. Recent human research by Berbari et al has further confirmed significant antiangiogenic effects using an oral preparation of liquid cartilage extract.
(Folkman J, et al. Cancer 1963;16:453; Folkman J. NEJM 1971;285:1182; Folkman J, Klagsburn M. Science. 1987;235:442-447; Davis PF, et al. Microvasc Res. 1997 Sep;54(2):178-182; Sheu JR, et al. Anticancer Res 1998 Nov-Dec;18(6A):4435-4441; Dupont E, et al. J Cutan Med Surg. 1998 Jan;2(3):146-152; Berbari P, et al. J Surg Res. 1999 Nov;87(1):108-113.)
The polysaccharides in both bovine and shark cartilage are said to have immune stimulating properties.
Shark cartilage contains 16% calcium and 8% phosphorous.
Tumor inhibiting properties are claimed for bovine cartilage in general.
» requirements:
RDA: None.
» food sources:
Generally taken in the form of dietary supplements derived from shark or bovine sources. Neither shark nor bovine cartilage is commonly obtained in significant amounts from dietary sources.
» deficiency:
Cartilage is not considered an essential nutrient and no deficiency pattern has been postulated.
» therapeutics:
Cancer: Cartilage, particularly shark cartilage has gained significant notoriety for its claimed benefit in the prevention and treatment of various forms of cancer. In the 1980s John Prudden investigated the use of bovine tracheal cartilage in immune enhancement and treatment of tumors. Dr. Prudden published a 31 patient case series in which he recorded significant results in a wide variety of intractable malignancies including, pancreatic cancer, metastatic breast cancer, and glioblastoma multiforme. Some of these patients had been followed for more than five years at the time the case series was published in 1985, and some were still alive in 1995 with follow-up approaching 20 years. In 1994, Puccio et al published an abstract reporting a clinical trial of bovine cartilage in 35 patients with metastatic renal cell carcinoma. 22 of the 35 patients had completed three months of therapy and were evaluable for response. Of these 22, there were three objective responses, none of whom had relapsed with follow-up of 6+, 12+, and 30+ months. There were also two patients with stable disease.
However, by 1992 William Lane's publication of the popular book "Sharks Don't Get Cancer" shifted the focus and catalyzed a wide debate in public and professional circles as to the potential therapeutic efficacy of shark cartilage extracts based primarily upon laboratory evidence that substance effectively inhibits angiogenesis. Overall, advocates of bovine cartilage tend to emphasize immune modulation effects, while those using shark cartilage emphasize angiogenesis inhibition. Specifically, Lane and others have proposed that shark cartilage acts as an inhibitor and modulator of blood vessel development in tumors. Once atrophied, failed capillaries theoretically cannot be replaced, thus causing necrosis in the tumor. Therefore, the shark cartilage would appear to have the ability to reduce tumor growth and also induce tumor necrosis. Lane has frequently cited a 16 week clinical trial in Cuba involving 29 terminal cancer patients using shark cartilage as the only therapy. The patients were all hospitalized and doctors and nurses were in constant attendance during the study. These patients included six breast, five prostate, five central nervous system (brain), two stomach, two liver, two ovarian, two uterus, two esophageal, two tonsil and one urinary bladder stage II or IV cases. Eight died during the 16 week study, and six have died shortly after the study was completed. Fifteen of the 29 patients, diagnosed as terminal before the study began, were still alive a year later.
In a 1998 study by Miller at al of the Cancer Treatment Centers of America involving 60 patients with advanced cancer, including cancer of the breast, colon or rectum, prostate, and brain, or non-Hodgkin's lymphoma, shark cartilage did not appear to offer significant benefit. Phase III clinical trials involving 550 patients with small-cell lung cancer were initiated in December 1998 under the auspices of the National Cancer Institute using Neovastat, a liquid antiangiogenesis drug made from shark cartilage. Another large study at the Mayo Clinic to test shark cartilage on 600 patients with life-threatening breast and colon cancer will soon for the near future.
(Prudden JF. J Biol Res Mod 1985;4:551-584; Romano CF, et al. J Biol Response Mod 1985 Dec;4(6):585-589; Miller DR, et al. J Clin Oncol 1998 Nov;16(11):3649-3655.)
Macular degeneration: Shark cartilage has been used in the treatment of macular degeneration based upon its presumed ability to inhibit the excessive growth of blood vessels in the eye. In an often-cited 1983 study, Lee and Langer of MIT placed cartilage extract next to tumor tissue and implanted both into eyes of laboratory rabbits. In contrast to the normal pattern in which blood vessels from the cornea grow toward tumors, those treated with shark cartilage showed surprisingly little capillary growth.
(Lee A, Langer R. Science 1983 Sep 16;221(4616):1185-1187; Langer R, et al. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4331-4335.)
Osteoarthritis and Rheumatoid Arthritis: Cartilage is often claimed as an effective agent in the treatment of arthritis based upon its anti-inflammatory action and its ability to facilitate joint rebuilding by providing necessary constituents. While evidence demonstrating cartilage's value in promoting wound healing and reducing inflammation has been building for decades, the bioavailability of the chondroitin sulfate in the cartilage and its clinical efficacy have been questioned.
(Prudden JF, Balassa LL. Semin Arthritis Rheum. 1974 Summer;3(4):287-321.)
Psoriasis: Immune-modulating and anti-inflammatory functions may help alleviate symptoms.
(Fontenele JB, et al. Braz J Med Biol Res. 1996 May;29(5):643-646; Dupont E, et al. J Cutan Med Surg. 1998 Jan;2(3):146-152.)
Regional enteritis (Crohn's disease): Immune-modulating and anti-inflammatory functions may help alleviate symptoms.
(Prudden JF, Balassa LL. Semin Arthritis Rheum. 1974 Summer;3(4):287-321.)
Wound healing: Starting in 1954 with a study published by John Prudden and associates researchers demonstrated that wound healing could be enhanced by inserting chips of bovine tracheal cartilage inserted into wounds, demonstrated that cartilage enhances wound healing. Subsequent research found that cartilage was particularly effective in reversing steroid-induced inhibition of wound healing.
(Prudden JF, Allen J. JAMA 1965;192:352-356; Prudden JF, Wolarsky E. Surg Gyn Obstet 1967;125(7):109-113.)
» dosage:
Maintenance dose: A typical supplemental dose for either form of cartilage is 750 mg, as powder or in capsules, three to four times daily.
Therapeutic dose: Doses three times higher are commonly used by individuals with cancer to complement their conventional treatment. Experimental protocols using shark cartilage for cancer treatment have often used doses higher 50-90 grams per day orally or by enema. Cancer therapy using bovine tracheal cartilage usually consists of taking three grams three times per day in the form of capsules.
» side effects: Nausea, as well as vomiting and constipation, is a common side effect reported by individuals taking cartilage supplements. For those taking shark cartilage the large volume commonly ingested, the strong fish-like odor and a taste often considered highly unpleasant taste combine to make the supplement initially challenging for some users. Intolerance to shark cartilage has been reported in clinical studies by Miller et al and others. Recent advances in shark cartilage production techniques have significantly reduced the adverse odor and taste.
(Miller DR, et al. J Clin Oncol 1998 Nov;16(11):3649-3655.)
» toxicity:
Concern has been raised that the large volume of cartilage commonly consumed could be toxic due to high levels of calcium ingested. Thus far, however, no substantial pattern of adverse events due to calcium toxicity has been documented. Digestive side effects are the primary confirmed form of toxicity. Supplementation with potassium and magnesium could help prevent any such mineral imbalance.
The FDA has not approved shark or bovine cartilage for safety or effective.
Several years ago the National Cancer Institute cancelled clinical trials of shark cartilage when laboratory analyis showed that the cartilage supplements it was testing were contaminated. No definitive evidence exists as to the current status of product quality or purity for supplemental forms currently available.
» contraindications: A variety of sources have asserted that certain individuals might suffer adverse effects from consumption of cartilage products. These populations include: children, woman who are pregnant or planning on becoming so in the near future, individuals who have had surgery within the past 30 days or are planning on having surgery, individuals with a history of cardiovascular disease or recent heart attack, and athletes undergoing intensive physical training. These cautions, however, are based on theoretical concerns, not on clinical research, case reports, or other substantive evidence.
» interactions:
No adverse interactions between cartilage (shark or bovine) have been reported or proven. At this time both forms of cartilage are generally considered to have minimal risk of interfering with pharmaceutical medications.
McGuire and others have proposed that cartilage supplementation could be combined with conventional therapies, such as tamoxifen, to achieve a synergistic effect.
(McGuire TR, et al. Pharmacotherapy 1994;14(3):362.)
Footnotes
[No authors listed] AE 941--Neovastat. Drugs R D. 1999 Feb;1(2):135-136.
[No authors listed] NCI to sponsor phase III trials of liquid shark cartilage angiogenesis inhibitor. Oncology (Huntingt). 1999 Jan;13(1):82.
Allen J, Prudden JF. Histologic response to a cartilage powder preparation in a controlled human study. Am J Surg 1966 Dec;112(6):888-891.
Ashar B, Vargo E. Shark cartilage-induced hepatitis. Ann Intern Med. 1996 Nov 1;125(9):780-781.
Atassi G. Investigation of the antitumor effect of shark cartilage on human xenografts in nude mice. 1989 Sept 1. Institute Jules Bordet. Brussels. (Unpublished)
Bartolucci C, Cellai L, Iannelli MA, Lamba D, Liverani L, Mascellani G, Perola E. Inhibition of human leukocyte elastase by chemically and naturally oversulfated galactosaminoglycans. Carbohydr Res. 1995 Oct 23;276(2):401-408.
Berbari P, Thibodeau A, Germain L, Saint-Cyr M, Gaudreau P, El-Khouri S, Dupont E, Garrel DR. Antiangiogenic effects of the oral administration of liquid cartilage extract in humans. J Surg Res. 1999 Nov;87(1):108-113.
Blackadar CB. Skeptics of oral administration of shark cartilage. J National Cancer Institute 1993 Dec 1;85(23):1961-1962.
Brem H, Folkman J. Inhibition of tumor angiogenesis mediated by cartilage. J Exp Med. 1975 Feb 1;141(2):427-439.
D'Amore P. Angiogenesis as a strategy for antimetastasis. Seminars in Thrombosis and Hemostasis. 1988;14(1):73-78.
D'Amore P, Klagsbrun M. Angiogenesis factors and mechanisms from the pathobiology of neoplasia. Ed. Alphonse E. Sirica. Plenum Pub Corp., 1989, 513-531.
Davis PF, He Y, Furneaux RH, Johnston PS, Ruger BM, Slim GC. Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvasc Res. 1997 Sep;54(2):178-182.
Dupont E, Savard PE, Jourdain C, Juneau C, Thibodeau A, Ross N, Marenus K, Maes DH, Pelletier G, Sauder DN. Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis. J Cutan Med Surg. 1998 Jan;2(3):146-152.
Abstract: BACKGROUND: A number of inflammatory and immune diseases are associated with vascular changes. Psoriasis, as an example, is a common inflammatory skin disease with dilation of capillaries as an early histological change. In more developed psoriatic lesions there is proliferation of blood vessels and neovascularization. The use of agents that target these vascular changes represents a novel therapeutic strategy in the treatment of inflammatory diseases. Since cartilage is an avascular tissue, it has been hypothesized that there may be factors found in cartilage that inhibit blood vessel formation. OBJECTIVE: The objectives of this study were 1) to determine whether extracts of cartilage could inhibit angiogenesis, and 2) since altered angiogenesis is associated with certain diseases, including psoriasis, to examine whether inhibition of angiogenesis could potentially contribute to the treatment of psoriasis. METHODS: Extracts of shark cartilage were prepared by homogenization and ultrafiltration to derive the active agent termed AE -941. This agent was tested for antiangiogenesis activity using the embryonic vascularization test, which is a modification of the ex vivo chick embryo culture (CAM). Since one of the first steps in angiogenesis is degradation by metalloproteinases of the basement membrane of capillaries, AE -941 was tested for collagenase activity using a fluorogenic peptide substrate. Anti-inflammatory properties were tested using a cutaneous irritation model in humans. RESULTS: A dose dependent inhibition in embryonic neovascularization as well as in collagenase activity by AE -941 was demonstrated. When test compounds were applied on the forearms of test subjects, AE -941 was shown to have anti-inflammatory properties. Anecdotal data suggested that topical AE -941 had a beneficial effect in psoriasis. CONCLUSION: Our results show that AE -941 has anti-angiogenic and anti-inflammatory properties. Antiangiogenesis agents such as AE -941 provide an entirely new class of agents to treat cutaneous and systemic diseases associated with altered vascularity.
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. 1985 Dec;4(6):590-595.
Abstract: Catrix is an acidic mucopolysaccharide complex derived from bovine tracheal cartilage. The antitumor efficacy of Catrix has been evaluated in the human tumor stem cell assay system using three human tumor cell lines and fresh biopsy specimens from 22 patients with malignant tumors. In vitro efficacy has been demonstrated with high dose continuous exposure Catrix, particularly against the 8226 human myeloma cell line as well as ovarian, pancreatic, colon, testicular, and sarcoma biopsy specimens. The level of sensitivity was at less than or equal to 30% survival of colony growth in vitro. Since the in vitro concentrations may be achievable in vivo, the results justify more detailed in vitro evaluation as well as potential clinical trials.
Felzenszwalb I, Pelielo de Mattos JC, Bernardo-Filho M, Caldeira-de-Araujo A. Shark cartilage-containing preparation: protection against reactive oxygen species. Food Chem Toxicol. 1998 Dec;36(12):1079-1084.
Abstract: There is overwhelming evidence to indicate that free radicals cause oxidative damage to lipids, proteins and nucleic acids and are involved in the pathogenesis of several degenerative diseases. Therefore, antioxidants, which can neutralize free radicals, may be of central importance in the prevention of these disease states. The protection that fruits and vegetables provide against disease has been attributed to the various antioxidants contained in them. Recently, an anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage has been described. Using electrophoretical assays, bacteria survival and transformation and the Salmonella/mammalian-microsome assay, we investigated the putative role of shark cartilage-containing preparation in protecting cells against reactive oxygen species induced DNA damage and mutagenesis. If antimutagens are to have any impact on human disease, it is essential that they are specifically directed against the most common mutagens in daily life. Our data suggest that shark cartilage-containing preparation can play a scavenger role for reactive oxygen species and protects cells against inactivation and mutagenesis.
Folkman J, et al. Cancer 1963;16:453.
Folkman J. NEJM 1971;285:1182.
Folkman J, Klagsburn M. Angiogenic factors. Science. 1987;235:442-447.
Folkman J, Cotran R. Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol. 1976;16:207-248. (Review)
Folkman J. The vascularization of tumors. Sci Am. 1976 May;234(5):58-64, 70-73.
Fontenele JB, Viana GS, Xavier-Filho J, de-Alencar JW. Anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage. Braz J Med Biol Res. 1996 May;29(5):643-646
Fontenele JB, Araujo GB, de Alencar JW, Viana GS. 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. 1997 Nov;20(11):1151-1154.
Harshbarger JC. 91st Annual Meeting American Association for Cancer Research. 2000 Apr 5. (Abstract)
Abstract: Harshbarger, of George Washington University, who heads the federally sponsored Registry of Tumors in Lower Animals, described 40 cases of tumors that have been found in sharks and their close cousins, the skates, rays and chimerids. Harshbarger said that 23 of the 40 tumors in the registry are in sharks, while the rest are in their close relatives. The bodies of all these creatures contain cartilage but no bone. He said 12 or 13 of the 40 tumors were malignant, while the rest were benign, and six of the malignant tumors were in sharks.
Horsman MR, Alsner J, Overgaard J. The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma. Acta Oncol 1998;37(5):441-445.
Abstract: This study was designed to investigate the potential of shark cartilage extracts to inhibit the growth and metastatic spread of a murine solid tumour. The SCCVII carcinoma, implanted in the right rear foot of C3H mice, was used. Following tumour implantation, two different commercially available extracts of shark cartilage (Sharkilage and MIA Shark Powder) were dissolved in water and orally administered to the mice at doses that ranged from 5 to 100 mg per mouse. These injections were repeated on a daily basis for up to 25 days post-implantation of the primary tumour. Compared to non-drug-treated animals, daily administration of the shark cartilage extracts did not show any adverse toxicity (as measured by changes in body weight and lethality). More importantly, none of the shark cartilage doses tested had any retarding effect on the growth of the primary tumour, nor did they inhibit the development of metastases seen in the lungs of the tumour-bearing mice at autopsy. In conclusion, our results offer no support for the proposed use of shark cartilage extracts as an anti-cancer therapy.
Hunt TJ, Connelly JF. Shark cartilage for cancer treatment. Am J Health-System Pharm 1995 August 15;52:1756,1760.
Lane AW, Contreras E Jr. High rate of bioactivity (reduction in gross tumor size) observed in advanced cancer patients treated with shark cartilage material. J Naturopathic Med 1992;3:86-88.
Lane IW, Comac L. Sharks Don't Get Cancer: How Sharks Cartilage Could Save Your Life. Avery, 1992.
Lane IW. 60 Minutes. July 11, 1993 transcript.
Langer R, Conn H, Vacanti J, Haudenschild C, Folkman J. Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4331-4335.
Abstract: Angiogenesis and tumor growth were inhibited in two different animal models by regional infusion of a partially purified cartilage extract. In rabbits bearing corneal implants of V2 carcinoma and receiving the inhibitor, vascular growth rates were < 3% of those in control animals receiving either Ringer's solution or bovine trypsin inhibitor (Trasylol). Subconjunctival B16 melanoma implants in mice receiving the inhibitor weight < 2.5% of implants in mice receiving Ringer's solution, Trasylol, or albumin. Histologic study of major organs and standard blood tests revealed no toxic effects in any of the animals. The inhibitor did not retard the growth of either tumor cell type in tissue culture at concentrations as high as 1 mg/ml. These results suggest that the cartilage factor does not interfere with the growth of the tumor cell population directly but that it prevents tumor growth by inhibiting angiogenesis.
Langer R, Brem H, Falterman K, Klein M, Folkman J. Isolations of a cartilage factor that inhibits tumor neovascularization. Science. 1976 Jul 2;193(4247):70-72.
Abstract: A cartilage fraction isolated by guanidine extraction and purified by affinity chromatography inhibits tumor-induced vascular proliferation and consequently restricts tumor growth. This fraction contains several different proteins; the major one has a molecular weight of about 16,000. The fraction strongly inhibits protease activity.
Lee A, Langer R. Shark cartilage contains inhibitors of tumor angiogenesis. Science 1983 Sep 16;221(4616):1185-1187.
Abstract: Shark cartilage contains a substance that strongly inhibits the growth of new blood vessels toward solid tumors, thereby restricting tumor growth. The abundance of this factor in shark cartilage, in contrast to cartilage from mammalian sources, may make sharks an ideal source of the inhibitor and may help to explain the rarity of neoplasms in these animals.
Mathews J. Media feeds frenzy over shark cartilage as cancer treatment. J National Cancer Institute 1993 Aug 4;85(15):1190-1191.
Mathews J. Sharks still intrigue cancer researchers. J National Cancer Institute 1992 July 1;84(13):1000-1002.
McGuire TR, Kazakoff PW, Hoie EB, Fienhold MA. Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium. Pharmacotherapy. 1996 Mar-Apr;16(2):237-244.
McGuire TR, et al. Tamoxifen and shark cartilage: potential anti-angiogenic combination. (Abstract from American College of Clinical Pharmacy Annual Meeting St. Louis, 1994) Pharmacotherapy 1994;14(3):362.
Miller DR, Anderson GT, Stark JJ, Granick JL, Richardson D. Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer. J Clin Oncol 1998 Nov;16(11):3649-3655.
Abstract: PURPOSE: Patients with cancer and chronic inflammatory disorders have used shark cartilage (SC) preparations for many years. Preclinical studies that support their beneficial effects are scanty, and reports of clinical trials have been anecdotal. The proposed mechanisms of antitumor action include direct or indirect inhibition of angiogenesis. Because of the emerging use of SC as an alternative to conventional cancer therapy, this trial was launched to evaluate the safety and efficacy of SC. PATIENTS AND METHODS: Sixty adult patients with advanced previously treated cancer (breast, 16 patients; colorectal, 16 patients; lung, 14 patients; prostate, eight patients; non-Hodgkin lymphoma, three patients; brain, one patient; and unknown primary tumor, two patients) were enrolled. Eligibility criteria included confirmation of diagnosis, resistance to conventional therapy, objective measurable disease, life expectancy of 12 weeks or greater, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, no recent or concomitant anticancer therapy, no prior SC, and informed consent. Patients underwent evaluation of the extent of disease, quality-of-life score (Functional Assessment of Cancer Therapy-General [FACT-G] scale), and hematologic, biochemical, and selected immune function studies at baseline and after 6 and 12 weeks of SC therapy. The dose of SC was 1 g/kg daily orally in three divided doses. Standard criteria were used to evaluate adverse events and response. RESULTS: Ten of 60 patients were lost to follow-up(LTFU) or refused further treatment (RFT) before the 6-week evaluation and were not assessable for toxicity and response. Three patients with stable disease at 6 weeks were LTFU or RFT thereafter. Of the 47 fully assessable patients, five were taken off study because of gastrointestinal toxicity or intolerance to SC. Progressive disease (PD) at 6 or 12 weeks occurred in 22 and five patients, respectively. Five patients died of PD while undergoing SC therapy. No complete (CRs) or partial responses (PRs) were noted. Median time to tumor progression in the entire study population was 7+/-9.7 weeks (mean, 11.4 weeks; range, 3.7 to 45.7 weeks). Ten (20%) of 50 assessable patients, or 16.7% of the 60 intent-to-treat patients, had stable disease (SD) for 12 weeks or more. The median time to tumor progression was 27 weeks, the mean was 28.8+/-9.9 weeks, and the range was 18.6 to 45.7 weeks. In this subset, FACT-G scores improved in four patients, were unchanged in four patients, and declined in two patients. Twenty-one adverse events (grade 1, eight events; grade 2, seven events; and grade 3, six events) were recorded, 14 of which were gastroenterologic (nausea, vomiting, constipation). CONCLUSION: Under the specific conditions of this study, SC as a single agent was inactive in patients with advanced-stage cancer and had no salutary effect on quality of life. The 16.7% rate of SD was similar to results in patients with advanced cancer treated with supportive care alone.
Moses MA. A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clin Exp Rheumatol. 1993 Mar-Apr;11 Suppl 8:S67-69. (Review)
Moses M, Sudhalter, Langer R. Identification of an inhibitor of neovascularization from cartilage. Science 1990;248:1408-1410.
Moses MA, Wiederschain D, Wu I, Fernandez CA, Ghazizadeh V, Lane WS, Flynn E, Sytkowski A, Tao T, Langer R. Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci USA. 1999 Mar 16;96(6):2645-2650.
Abstract: Cartilage is an avascular and relatively tumor-resistant tissue. Work from a number of laboratories, including our own, has demonstrated that cartilage is an enriched source of endogenous inhibitors of angiogenesis. In the course of a study designed to identify novel cartilage-derived inhibitors of new capillary growth, we have purified an inhibitory protein that was identified by peptide microsequencing and protein database analysis as troponin I (TnI). TnI is a subunit of the troponin complex (troponin-C and troponin-T being the other two), which, along with tropomyosin, is responsible for the calcium-dependent regulation of striated muscle contraction; independently, TnI is capable of inhibiting actomyosin ATPase. Because troponin has never previously been reported to be present in cartilage, we have cloned and expressed the cDNA of human cartilage TnI, purified this protein to apparent homogeneity, and demonstrated that it is a potent and specific inhibitor of angiogenesis in vivo and in vitro, as well as of tumor metastasis in vivo.
Newman V, Rock CL, Faerber S, Flatt SW, Wright FA, Pierce JP. Dietary supplement use by women at risk for breast cancer recurrence. The Women's Healthy Eating and Living Study Group. J Am Diet Assoc. 1998 Mar;98(3):285-292.
Oikawa T, Ashino-Fuse H, Shimamura M, Koide U, Iwaguchi T. A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Lett. 1990 Jun 15;51(3):181-186.
Ono M, Izumi H, Yoshida S, Goto D, Jimi S, Kawahara N, Shono T, Ushiro S, Ryuto M, Kohno K, Sato Y, Kuwano M. Angiogenesis as a new target for cancer treatment. Cancer Chemother Pharmacol. 1996;38 Suppl:S78-82. (Review)
Abstract: Neovascularization is often required for rapid growth of solid tumors and also limits vascular metastasis of tumor cells. Neovascularization-targeting agents are a recent innovation that may be a novel means of anticancer therapy. These antiangiogenic drugs have been developed by targeting cell proliferation of vascular endothelial cells, basement-membrane-degrading enzymes, angiogenic factors/receptors, extracellular matrix, angiogenesis signaling, and cell-cell/cell-matrix interactions. In this report, we describe how tumor angiogenesis occurs and how antiangiogenic agents are developed.
Pauli BU, Memoli VA, Kuettner KE. Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. J Natl Cancer Inst. 1981 Jul;67(1):65-73.
Pepper MS, Montesano R, Vassalli JD, Orci L. Chondrocytes inhibit endothelial sprout formation in vitro: evidence for involvement of a transforming growth factor-beta. J Cell Physiol. 1991 Jan;146(1):170-179.
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. 1974 Summer;3(4):287-321.
Prudden JF, Allen J. The clinical acceleration of healing with a cartilage application. JAMA 1965;192:352-356.
Prudden JF, Wolarsky E. The reversal by cartilage of the steroid-induced inhibition of wound healing. Surg Gyn Obstet 1967;125(7):109-113.
Prudden JF. The treatment of human cancer with agents prepared from bovine cartilage. J Biol Res Mod 1985 Dec;4(6):551-584.
Abstract: Oral and subcutaneous administration of specific preparations of bovine tracheal cartilage rings (Catrix), a nontoxic agent, has resulted in a high response rate in 31 cases of a variety of clinical malignancies (response rate 90%, 61% complete). The demonstrated responder include present therapeutic disasters such as glioblastoma multiforme and cancers of the pancreas and lung. Other types which were treated with success included cancers of the ovary, rectum, prostate, cervix, thyroid, and an inoperable squamous cancer of the nose. These responses were observed when full dose therapy was given over prolonged courses of treatment (years). This wide range of Catrix efficacy now invites investigation by others to confirm the effectiveness of the material and to isolate the molecular entities responsible for these unexpectedly favorable results.
Puccio C, Mittelman A, Chun H, Baskind P, Ahmed T. Treatment of metastatic renal cell carcinoma with Catrix. Proc Annu Meet Am Soc Clin Oncol 1994;13:A769. (Abstract)
Abstract: Catrix is an acidic mucopolysaccharide complex derived from bovine tracheal cartilage which has demonstrated immunostimulatory and antimitotic activity in both in vitro and in vivo models. Formulations include an injectable 5% solution and oral capsule 375 mg. Four different schedules were evaluated in patients (pts) with metastatic renal cell carcinoma. Of the 35 pts enrolled, 22 were evaluable for response (completing greater than 3 mo of therapy). Results are shown in a table. Ten of the 22 evaluable pts were not previously treated with any systemic therapy; all 3 responders (and 1 SD) occurred in the subset of untreated pts. Lungs were the major site of response with disappearance of lesions (2) and greater than 50% shrinkage (1); minor responses noted in liver (1) and kidney (1). Duration of response is 30+ mo, 12+ mo and 6+ mo in the 3 PRs. Toxicity was mild (Grade I) and included dysgeusia (8), fatigue (3), dyspepsia (2), nausea (2), fever (2), dizziness (1), and scrotal edema (1). Our results suggest that Catrix is very well tolerated and may be active in previously untreated pts with metastatic renal cell carcinoma. Further accrual of pts is warranted.
Romano CF, Lipton A, Harvey HA, Simmonds MA, Romano PJ, Imboden SL. A phase II study of Catrix-S in solid tumors. J Biol Response Mod 1985 Dec;4(6):585-589.
Abstract: Catrix-S is an acidic mucopolysaccharide complex derived from bovine tracheal cartilage. This material was administered by weekly subcutaneous injection (5.0-7.5 g/week) to nine patients with progressive metastatic malignancy. One complete response was seen in a patient with metastatic renal cell carcinoma to the lungs. Eight patients had progression of their disease. No undue toxicity and no consistent immunologic alteration was noted.
Rosen J, Sherman WT, Prudden JF, Thorbecke GJ. Immunoregulatory effects of catrix. J Biol Response Mod 1988 Oct;7(5):498-512.
Abstract: The immunoregulatory effect of Catrix on in vitro and and in vivo antibody production was examined in mice. Catrix, an acidic mucopolysaccharide complex, contains glycosaminoglycans including chondroitin sulfate. Catrix-S, a soluble derivative, was found to enhance T-dependent and T-independent antibody responses in vivo in a dose-dependent manner, with 100 mg intraperitoneally or 10 mg intravenously being optimal. Lower doses were found to be less effective or inhibitory. In vitro, the enhancing activity of Catrix-S on proliferative response was additive with that of dextran sulfate and lipopolysaccharide but not with chondroitin sulfate C. This immunoaugmenting activity appears to be related to the chondroitin sulfate component of Catrix-S, because both have similar effects on in vivo and in vitro antibody responses and because chondroitinase ABC inactivates activity. The inhibitory activity of Catrix-S could be separated from its stimulatory effects by ammonium sulfate precipitation or by fractionation according to molecular weight. The immunoaugmenting effect was present in the 0-30% saturated ammonium sulfate precipitate and in the 5-10,000-m.w. and 30-100,000-m.w. fractions. The ability of Catrix-S to enhance antibody responses in nude as well as in normal mice, and antibody responses to T-independent as well as to T-dependent antigens, indicates that its activity is due in part to a direct effect on B cells and/or to an indirect effect mediated by macrophages.
Sheu JR, Fu CC, Tsai ML, Chung WJ. Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities. Anticancer Res 1998 Nov-Dec;18(6A):4435-4441.
Abstract: BACKGROUND: A potent angiogenesis inhibitor, U-995, has been purified from the cartilage of the blue shark (Prionace glauca). U-995 is composed of two single peptides with molecular mass of 10 and 14 kDa, respectively. MATERIALS AND METHODS: U-995 was designed to study human umbilical vein endothelial cell (HUVEC) migration and proliferation in vitro and angiogenesis induced by TNF alpha in chicken chorioallantoic membrane (CAM). Furthermore, we determined the ability of U-995 to inhibiting tumor cell growth and metastasis. RESULTS: U-995 (15 and 30 micrograms/ml) markedly inhibited HUVEC migration and, at 15-50 micrograms/ml produced a dose-dependent decline in [3H]-thymidine incorporation. 30 and 50 micrograms/ml of U-995, when added to TNF alpha-induced angiogenesis caused discontinuous and disrupted blood vessels. Moreover, U-995 (30 micrograms/ml) markedly prevented collagenase-induced collagenolysis. In addition, when 200 micrograms U-995 was injected i.p. into mice it suppressed sarcoma-180 cell growth and B16-F10 mouse melanoma cell metastasis in vivo. CONCLUSIONS: These results suggest that the anti-angiogenic effects of U-995 may be be due to interference with the proliferation and migration of HUVECs as well as inhibition of collagenolysis, thereby leading to inhibition of both angiogenesis and tumor cell growth.
Stetler-Stevenson W. Biological basis for neoadjuvant and adjuvant therapy: tumor invasion and metastasis (TIMP's). Neoadjuvant and Adjuvant Therapy for Selected Malignancies. Mar 5, 1993. UMDNJ.
Wolarsky ER Finke SR Prudden JF. Acceleration of wound healing with heterologous cartilage. Immunological considerations. Proc Soc Exp Biol Med 1966 Nov;123(2):556-561
Yutani Y, Kono T, Ishii M, Chanoki M, Chanoki Y, Asada K, Shimazu A, Hamada T. Alteration of cartilagenous proteoglycan in psoriasis. Clin Exp Dermatol. 1991 Jan;16(1):22-24.