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Back To Vidyya Alternative Medicine Cancer Fact Sheet:

Cartilage (Bovine and Shark)

Overview
General Information
History
Laboratory/Animal/Preclinical Studies
Human/Clinical Studies
Adverse Effects
Levels Of Evidence
Glossary Of Terms
References
For More Information



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. A glossary of scientific terms used in the summary appears just before the references. Terms defined in the glossary are marked in the text by hypertext links.

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; 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.
  • Only three human studies have been published to date, and the results are inconclusive about the effectiveness of cartilage as a treatment for cancer.
  • Additional clinical trials of cartilage as a treatment for cancer are now being conducted.



General Information

Bovine 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 14-21] 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 17,22] Although reports of malignant tumors in sharks are rare, a variety of cancers have been detected in these animals.[reviewed in 22-24] Nonetheless, several substances that have antitumor activity have been identified in cartilage.[25-48, reviewed in 2-4,6-10,16-21,49,50] More than a dozen clinical studies of cartilage as a treatment for cancer have already been conducted, [2-4,10-13, reviewed in 6-9,15-20] and additional clinical studies are now under way.[51,52, reviewed in 9,16]

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 28-31,36,37,50] 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 34,35,42,53-56] 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.[55] Inhibition of angiogenesis at this early stage may, in some instances, lead to complete tumor regression.[55] 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 21,30,31,40,50,56,57] Chondroitin sulfate is the major glycosaminoglycan in cartilage.[reviewed in 40,56] 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 (see Laboratory/Animal/Preclinical Studies section).[48] Other data indicate that most of the antiangiogenic activity in cartilage is not associated with the major structural components. [reviewed in 27,31,50]

Some glycosaminoglycans in cartilage reportedly have anti-inflammatory and immune system-stimulating properties,[58,59, reviewed in 1,2,14,17] 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 19] In the United States, dietary supplements are regulated as foods, not drugs. Therefore, premarket evaluation and approval by the 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 19] 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 19]

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 to study cartilage as a treatment for cancer.[10,51,52,60, reviewed in 20] 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.[21,40,41,44- 46,61, reviewed in 7-9,16,49] 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, reviewed in 29,48,50] 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, reviewed in 29,48,50]

In human studies, cartilage products have been administered topically or orally, or they have been given by enema or subcutaneous injection.[2-4,6,10-13,51,52, reviewed in 7-9,15-18,20] For oral administration, liquid, powdered, and pill forms have been used.[2-4,6,10-13,51,52, reviewed in 7- 9,15-18,20] 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.




History

The therapeutic potential of cartilage has been investigated for more than 30 years. As noted previously (General Information section), 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.[59, reviewed in 1,14,17,21]

Early studies of cartilage's therapeutic potential used extracts of bovine cartilage. The ability of these extracts to suppress inflammation was first described in the early 1960s.[59] The first report that bovine cartilage contains at least one angiogenesis inhibitor was published in the mid-1970s.[33] 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.[2,3,25,58]

In contrast, the first report that shark cartilage contains at least one angiogenesis inhibitor was published in the early 1980s,[39] and the only published report to date of a clinical trial of shark cartilage as a treatment for cancer appeared in the late 1990s.[10] 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. It has been estimated that 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 20] In addition, it has been estimated that, on a weight-for-weight basis, shark cartilage contains 1,000 times more antiangiogenic activity than bovine cartilage.[39, reviewed in 18]

As indicated previously (Overview and General Information sections), 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. There is only limited evidence to support the first two mechanisms of action; however, the evidence in favor of the third mechanism is more substantial (see Laboratory/Animal/Preclinical Studies section).

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 (VEGF).[reviewed in 53-56,62] Second, the "activated" endothelial cells must divide to produce new endothelial cells, which will be used to make the new blood vessels.[reviewed in 54,56,62-64] Third, the dividing endothelial cells must migrate toward the tumor.[reviewed in 54-56,62-64] 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 62-65] Fourth, the new endothelial cells must form the hollow tubes that will become the new blood vessels.[reviewed in 56,62] It is conceivable that some angiogenesis inhibitors may be able to block more than one step in this process.

It is important to note that cartilage is relatively resistant to invasion by tumor cells [reviewed in 30-32,35,36,38,48,50] and that tumor cells use matrix metalloproteinases when they migrate during the process of metastasis.[reviewed in 18,26,32,49,65] 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. It should also be noted that shark tissues other than cartilage have been reported to produce antitumor substances.[66-68, reviewed in 69]




Laboratory/Animal/Preclinical Studies

The antitumor potential of cartilage has been investigated extensively in laboratory and animal studies. Some of these studies have focused on the toxicity of cartilage products toward cancer cells in vitro.[25,42, reviewed in 2,3,16,18,45]

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 cartilage.[25, reviewed in 2,3,18] 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 to 5 milligrams per milliliter 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 its 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 bloodstream of patients who may be treated with either injected or oral formulations of this product. (See Human/Clinical Studies section 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 16,45] However, these results have not been published in a peer-reviewed, scientific journal.

In contrast, 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.[42] In this published study, the shark cartilage product was tested at only one concentration (0.75 milligrams per milliliter).[42]

The immune system-stimulating potential of cartilage has also been investigated in laboratory and animal studies, but just one study has been published in the peer-reviewed, scientific literature.[58] 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.[58] 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 milligrams per milliliter). Catrix® has also been reported to stimulate the activity of mouse macrophages in vivo, [reviewed in 2,18] 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.[5,26-31,33-37,39-43] Overall, these studies have revealed the presence of at least three angiogenesis inhibitors in bovine cartilage [26,27,30,31,35,37, reviewed in 29,50] and, in shark cartilage, of at least two.[41-43,48]

Three angiogenesis inhibitors in bovine cartilage have been very well characterized.[26,27,30,31,35,37, reviewed in 29,50] They are relatively small proteins with molecular masses that range from 23,000 to 28,000.[26,27,37, reviewed in 29] These proteins, called cartilage-derived inhibitor (CDI), cartilage-derived antitumor factor (CATF), and cartilage-derived collagenase inhibitor (CDCI) by the researchers who purified them,[26,27,35] have been shown to block endothelial cell proliferation in vitro and new blood vessel formation in the chorioallantoic membrane of chicken embryos.[27,30,31,35,37, reviewed in 29,50] Two of the proteins (CDI and CDCI) have been shown to inhibit matrix metalloproteinase activity in vitro,[26,27,31, reviewed in 29] and one (CDI) has been shown to inhibit endothelial cell migration in vitro.[27, reviewed in 29] These proteins do not block the proliferation of normal cells or of tumor cells in vitro.[27,30,35, reviewed in 29,50] 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.[26,27,31,37, reviewed in 50]

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.[28] This inhibitor, which has been named chondrocyte-derived inhibitor (ChDI), is a protein that has a molecular mass of approximately 36,000.[28] It has been reported that ChDI and CDI/TIMP-1 have similar antiangiogenic activities,[28, reviewed in 29,50] 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.[41] Both proteins have shown antiangiogenic activity when tested individually.[41] The exact relationship between these two 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.[41] It does not appear to inhibit the proliferation of other types of normal cells or of cancer cells in vitro.[41] 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.[41]

The second angiogenesis inhibitor identified in shark cartilage appears to have been studied independently by three groups of investigators.[42,43,48] This inhibitor, which was named SCF2 by one of the groups,[48] is a proteoglycan that has a molecular mass of less than 10,000. Proteoglycans are combinations of glycosaminoglycans and protein.[reviewed in 56] The principal glycosaminoglycan in SCF2 is keratan sulfate.[48] SCF2 has been shown to block endothelial cell proliferation in vitro,[42,43,48] the formation of new blood vessels in the chorioallantoic membrane of chicken embryos,[42,43] and tumor-induced angiogenesis in the cornea of rabbits.[42,43]

Other studies have indicated that AE-941/Neovastat®, the previously mentioned aqueous extract of shark cartilage, has antiangiogenic activity,[5, reviewed in 45] 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.[5, reviewed in 45] It may also inhibit the action of vascular endothelial growth factor (VEGF), thus interfering with the communication between tumor cells and nearby blood vessels.[47] AE-941/Neovastat® has also been reported to inhibit the growth of DA3 mammary adenocarcinoma cells and the metastasis of Lewis lung carcinoma cells in vivo in mice.[45,46, reviewed in 8,9,16,49] In the Lewis lung carcinoma experiments, AE-941/Neovastat® reportedly enhanced the antimetastatic effect of the chemotherapy drug cisplatin.[46, reviewed in 8,9,16,49] It is important to note, however, that most of the results obtained with AE-941/Neovastat® have not been published in peer-reviewed, scientific journals.

Additional in vivo studies of the antitumor potential of shark cartilage have been published in the peer-reviewed, scientific literature.[40,44,61] 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.[40] 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.[61]




Human/Clinical Studies

More than a dozen clinical studies of cartilage as a treatment for cancer have been conducted since the early 1970s.[2-4,10-13, reviewed in 6-9,15-20] However, results from only three studies have been published in peer-reviewed, scientific journals.[2,3,10] Although additional clinical studies are now under way,[51,52, reviewed in 9,16] the cumulative evidence to date is inconclusive regarding the effectiveness of cartilage as a cancer treatment in humans.

Two of the three published clinical studies evaluated the use of Catrix®, the previously mentioned (Laboratory/Animal/Preclinical Studies section) powdered preparation of bovine cartilage, as a treatment for various solid tumors.[2,3] One of these studies was a case series that included 31 patients;[2] the other was a phase II clinical trial that included nine patients.[3]

In the case series,[2] 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, hormone 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, 10 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 the majority of patients.

In the phase II trial,[3] 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 given 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. It was reported that one patient (with metastatic renal cell carcinoma) 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, ratio of helper T cells to cytotoxic T cells) was observed, although 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,[4] 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.[10] 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 10 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,[11,12] 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.[11] These three studies enrolled 20 patients with breast cancer,[11] 12 patients with prostate cancer,[11] and 12 patients with primary brain tumors.[12] All patients had been treated previously with conventional therapy. No other anticancer treatment was allowed concurrently with cartilage therapy. In two of the studies,[11] the name of the cartilage product was not identified; however, in the third study,[12] the commercially available product BeneFin® was used. Ten patients in each study completed at least 8 weeks of treatment and were, therefore, considered evaluable for response. No complete responses or partial responses were observed in any of the studies. Two patients in each study were reported to have stable disease that lasted 8 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.[6-9, reviewed in 15,16] However, results of these studies have been described only in abstracts presented at scientific conferences and in press releases by the manufacturer and not in peer-reviewed, scientific journals.

The exact number of clinical studies of AE-941/Neovastat® is difficult to determine because of inconsistencies in the information that is available. It appears that at least two clinical studies have been conducted: 1) a phase I/II trial of oral AE-941/Neovastat® as a single agent in 80 patients with advanced lung cancer and 72 patients with advanced prostate cancer, and 2) a study of oral AE-941/Neovastat® plus chemotherapy and/or radiation therapy in 126 patients with various types of solid tumors.[7-9,15,16] The phase I/II trial has been variously described as a single phase I/II study,[7-9,16] two phase I studies,[15,16], two phase II studies,[16] a study that involved only patients with advanced lung cancer,[7,8,16] and a study that involved both patients with advanced lung cancer and patients with advanced prostate cancer.[9]

It has been reported that AE-941/Neovastat® has little toxicity,[6-9,15,16,45,46] and there are indications from a retrospective analysis of data from the phase I/II trial that it may have anticancer activity in humans.[7] In addition, there is evidence from a randomized clinical trial that examined the effect of AE-941/Neovastat® on the angiogenesis associated with surgical wound repair that this extract contains at least one antiangiogenic component that is orally bioavailable.[70]

On the basis of laboratory, animal, and human data provided by the manufacturer, two randomized phase III trials of AE-941/Neovastat® in patients with advanced cancer have been approved by the FDA. In one trial, treatment with oral AE-941/Neovastat® plus chemotherapy and radiation therapy is being compared to treatment with placebo plus the same chemotherapy and radiation therapy in patients with stage III non-small cell lung cancer.[51] In the other trial, treatment with oral AE-941/Neovastat ® is being compared to treatment with placebo in patients with metastatic renal cell carcinoma.[52] Both trials are currently enrolling patients.




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 cartilage product Catrix®.[2-4] Nausea, vomiting, abdominal cramping and/or bloating, constipation, hypotension, hyperglycemia, generalized weakness, and hypercalcemia have been associated with the use of powdered shark cartilage.[10-12] The high level of calcium in shark cartilage may contribute to the development of hypercalcemia.[11,18] In addition, one case of hepatitis has been associated with the use of powdered shark cartilage.[71] Nausea and vomiting are the most commonly reported side effects following treatment with AE-941/Neovastat ®, the aqueous extract of shark cartilage.[7-9]




Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine

To assist readers in evaluating the results of human studies of CAM treatments for cancer, the strength of the evidence (i.e., the "levels of evidence") associated with each type of treatment is provided whenever possible. To qualify for a levels of evidence analysis, a study must 1) be published in a peer-reviewed, scientific journal; 2) report on a therapeutic outcome(s), such as tumor response, improvement in survival, or measured improvement in quality of life; and 3) describe clinical findings in sufficient detail that a meaningful evaluation can be made. 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. A table showing the levels of evidence scores for qualifying human studies cited in this summary is presented below. For an explanation of the scores and additional information about levels of evidence analysis of CAM treatments for cancer, please click on the following link: Levels of Evidence Analysis for Human Studies of Cancer Complementary and Alternative Medicine.

Cartilage (Bovine and Shark) Summary: Reference Numbers and the Corresponding Levels of Evidence

Reference Number Statistical Strength of Study Design Strength of Endpoints Measured Combined Score
2 3iii ­ Nonconsecutive Case Series Diii ­ Indirect Surrogates -- Tumor Response Rate 3iiiDiii
3 3iii ­ Nonconsecutive Case Series Diii ­ Indirect Surrogates -- Tumor Response Rate 3iiiDiii
10 3iii ­ Nonconsecutive Case Series Diii ­ Indirect Surrogates -- Tumor Response Rate 3iiiDiii



Glossary of Terms

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

acne: A disorder of the skin marked by inflammation of oil glands and hair glands.

adenocarcinoma: Cancer that begins in cells that line certain internal organs and that have glandular (secretory) properties.

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

anal: Having to do with the anus, which is the posterior opening of the large bowel.

angiogenesis: Blood vessel formation. Tumor angiogenesis is the growth of blood vessels from surrounding tissue to a sold tumor. This is caused by the release of chemicals by the tumor.

angiogenesis inhibitor: A substance that may prevent the formation of blood vessels. In anticancer therapy, an angiogenesis inhibitor prevents the growth of blood vessels from surrounding tissue to a solid tumor.

antiangiogenic: Refers to reducing the growth of new blood vessels.

antibody: A type of protein produced by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies disable antigens directly. Others make the antigen more vulnerable to destruction by white blood cells.

anti-inflammatory: Refers to reducing inflammation.

antimetastatic: Refers to reducing metastasis.

aqueous: Having to do with water.

arthritis: A disease marked by inflammation and pain in the joints.

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

B cells: White blood cells that develop from bone marrow and produce antibodies. Also called B lymphocytes.

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

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

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

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

cartilage: A type of connective tissue that contains cells (chondrocytes) surrounded by a tough but flexible matrix. The cartilage matrix is made of several types of the protein collagen and several types of proteoglycans, which are combinations of protein and long sugar molecules called glycosaminoglycans. Chondroitin sulfate is the major glycosaminoglycan in cartilage.

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

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

chemotherapy: Treatment with anticancer drugs.

chondrocytes: Cartilage cells. They make the structural components of cartilage.

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

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

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

cisplatin: An anticancer drug that belongs to the family of drugs called platinum compounds.

clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Clinical study reports can contain results for single patients (case reports) or many patients (case series or clinical trials).

clinical trial: A research study that evaluates the effectiveness of new interventions in people. Each study is designed to evaluate new methods of screening, prevention, diagnosis, or treatment of a disease.

collagen: A fibrous protein found in cartilage and other connective tissue.

collagenase: A type of enzyme that breaks down the protein collagen.

complementary and alternative medicine: CAM. Forms of treatment in addition to (complementary) or instead of (alternative) standard treatments. These practices include dietary supplements, megadose vitamins, herbal preparations, special teas, massage therapy, magnet therapy, spiritual healing, and meditation.

complete response: The disappearance of all signs of cancer. Also called a complete remission.

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

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

controlled study: An experiment or clinical trial that includes a comparison (control) group.

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

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

cultured cell line: Cells of a single type that have been grown in the laboratory for several generations (cell divisions).

cytotoxic: Cell-killing.

dermatitis: Inflammation of the skin.

diameter: The length of a straight line that extends from one edge of a tumor or other object that is circular or spherical in shape through its center and to the opposite edge. It is a measure of size.

dysgeusia: A bad taste in the mouth. Also called parageusia.

dyspepsia: Upset stomach.

edema: Swelling caused by excess fluid in body tissues.

embryo: Refers to an early stage in the development of a plant or an animal. In vertebrate animals, this stage lasts from shortly after fertilization until all major body parts appear. In particular, in humans, this stage lasts from about 2 weeks after fertilization until the end of the seventh or eighth week of pregnancy.

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

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

enzyme: A protein that speeds up the rate at which chemical reactions take place in the body.

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

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

gliosarcoma: A type of glioma.

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

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

hepatitis: Inflammation of the liver.

hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called hormone therapy or endocrine therapy.

hypercalcemia: Abnormally high blood calcium.

hyperglycemia: Abnormally high blood sugar

hypotension: Abnormally low blood pressure.

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

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

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

inflammation: A response of redness, swelling, pain, and a feeling of heat in certain areas, which is meant to protect tissues affected by injury or disease. intestine:

intraperitoneal: IP. Within the peritoneal cavity (the area that contains the abdominal organs).

intravenous: IV. Into a vein.

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

lymphocyte: White blood cells. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases.

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

malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and spread to other parts of the body.

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

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

metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors," and contain cells that are like those in the original (primary) tumor. The plural is metastases.

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

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

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

millimeter: A measure of length. A millimeter is approximately 26-times smaller than an inch.

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

molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms.

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

nonmalignant: Not cancerous.

oral: By or having to do with the mouth.

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

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

partial response: The shrinking, but not complete disappearance, of a tumor in response to therapy. Also called partial remission.

phase I trial: Phase I trials are the first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion, or injection), and the best dose. The drug is usually given in progressively higher doses to determine the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of treatments being tested, phase I trials usually include only a limited number of patients who have not been helped by other known treatments.

phase I/II trial: A trial to study the safety, dosage levels, and response to a new treatment.

phase II trial: Phase II trials focus on learning whether the new treatment has an anticancer effect (for example, whether it shrinks a tumor, or improves blood test results), and whether it is effective for a particular type of cancer.

phase III trial: Phase III trials compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates, and/or fewer side effects). In most cases, studies move into phase III trials only after a treatment shows promise in phases I and II. Phase III trials may include hundreds of people around the country or the world.

placebo: An inactive substance that looks the same as, and is administered in the same way as, a drug in a clinical trial.

polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically.

progressive disease: Cancer that is increasing in scope or severity.

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

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

quality of life : The overall enjoyment of life. Many clinical trials measure aspects of a person's sense of well-being and ability to perform various tasks in order to assess the effects that cancer and its treatment have on the person.

radiation therapy: The use of high-energy radiation from x-rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy) or from materials (radioisotopes) that produce radiation that are placed in or near a tumor or in the area where cancer cells are found (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy involves giving a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy.

randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments.

randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments. Neither the researcher nor the participant can choose the group. Using chance to assign people means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which of the treatments is best. It is the patient's choice to be in a randomized trial or not.

recurrent cancer: Cancer that has returned, at the same site as the original (primary) tumor or in another location, after the tumor had disappeared.

regional enteritis: Inflammation of the intestines, but usually only of the small intestine. Also called Crohn's disease.

regression: A decrease in the extent or size of cancer.

renal cell cancer: Cancer that develops in the lining of the renal tubules, which filter the blood and produce urine.

response: In medicine, an improvement related to treatment.

retrospective: Looking back at events that have already taken place.

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

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

scrotum: In males, the external sac that contains the testicles.

selection bias: An error in choosing the individuals or groups to take part in a study. Ideally, the subjects in a study should be very similar to one another and to the larger population (for example, all individuals with the same disease or condition) from which they are drawn. If there are important differences, the results of the study may not be valid.

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

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

stable disease: Cancer that is not decreasing or increasing in extent or severity.

stage: The extent of a cancer within the body, including whether the disease has spread from the original site to other parts of the body. Staging refers to the determination of the extent of cancer.

stage III non-small cell lung cancer: Cancer has spread to structures near the lung; to the lymph nodes in the area that separates the two lungs (mediastinum); or it has spread to the lymph nodes on the other side of the chest or in the neck. Stage III is further divided into stage IIIA (usually can be resected) and stage IIIB (usually cannot be resected).

subcutaneous: Beneath the skin.

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

therapeutic: Used to treat disease and help healing take place.

topical: On the surface of the body.

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

vascular endothelial growth factor: Also known as VEGF. A substance made by cells that stimulates new blood vessel formation.

white blood cell: Refers to cells in the immune system that help the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others.




References:

1. Prudden JF, Balassa, LL: The biological activity of bovine cartilage preparations. Seminars in Arthritis and Rheumatism 3(4): 287-321, 1974.

2. Prudden JF: The treatment of human cancer with agents prepared from bovine cartilage. Journal of Biological Response Modifiers 4: 551-584, 1985.

3. Romano CF, Lipton A, Harvey HA, et al.: A phase II study of Catrix-S in solid tumors. Journal of Biological Response Modifiers 4(6): 585-589, 1985.

4. Puccio C, Mittelman A, Chun P, et al.: Treatment of metastatic renal cell carcinoma with Catrix. Proceedings of the American Society of Clinical Oncology 13: A769, 1994.

5. Dupont E, Savard PE, Jourdain C, et al.: Antiangiogenic properties of a novel shark cartilage extract: Potential role in the treatment of psoriasis. Journal of Cutaneous Medicine and Surgery 2(3): 146-152, 1998.

6. Rivere M, Latreille J, Falardeau P, et al.: AE-941(Neovastat), an inhibitor of angiogenesis: Phase I/II lung cancer clinical trial results. Annals of Oncology 9(suppl. 4):133(A636P), 1998.

7. Evans WK, Latreille J, Batist G, et al.: AE-941, an inhibitor of angiogenesis: Rationale for a phase III study on AE-941 in combination with induction chemotherapy/radiotherapy in patients with non small cell lung cancer (NSCLC). Proceedings of the 1999 AACRNCIEORTC International Conference. Clinical Cancer Research 5: 3774s(A221), 1999.

8. Evans W, Latreille J, Batist G, et al.: AE-941, an inhibitor of angiogenesis: Rationale for development in combination with induction chemotherapy/radiotherapy in patients with non small cell lung cancer (NSCLC). Proceedings of the American Society of Clinical Oncology 18: A1938, 1999.

9. Evans WK, Latreille J, Barist G, et al.: AE-941, an inhibitor of angiogenesis: Rationale for development in combination with induction chemotherapy/radiotherapy in patients with non-small-cell lung cancer (nsclc). European Journal of Cancer 35(suppl. 4): S250(A992), 1999.

10. 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. Journal of Clinical Oncology 16(11): 3649-3655, 1998.

11. 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. Proceedings of the American Society of Clinical Oncology 17: A240, 1998.

12. Rosenbluth RJ, Jennis AA, Cantwell S, et al.: Oral shark cartilage in the treatment of patients with advanced primary brain tumors. A phase II pilot study. Proceedings of the American Society of Clinical Oncology 18: A554, 1999.

13. PDQ Clinical Trials Database (URL: http://cancernet.nci.nih.gov): Phase II study of the safety and efficacy of bovine tracheal cartilage in the treatment of advanced or metastatic cancer. Protocol IDs: MRMC-CTCA-9506, NCI-V96-1027. Status: Closed. Database accessed: July 10, 2000.

14. Prudden JF, Migel P, Hanson P, et al.: The discovery of a potent pure chemical wound-healing accelerator. The American Journal of Surgery 119(5): 560-564, 1970.

15. Anonymous: Aetema: Clinical results from phase I of the prostate and lung cancer study confirm the safety of AE-941/Neovastat (press release). European Journal of Cancer Care 8: 7, 1999.

16. Anonymous: AE 941-Neovastat : Adis comments. Drugs R&D 1(2):135-136, 1999.

17. Cassileth BR: Shark and bovine cartilage therapies. In: The Alternative Medicine Handbook (WW Norton & Company, New York, NY), pp. 197- 200, 1998.

18. The Center for Alternative Medicine Research in Cancer at the University of Texas-Houston Health Science Center: Cartilage summary. URL: http://www.sph.uth.tmc.edu:8052/utcam/agents/crtlg.htm. Date accessed: August 18, 2000.

19. Holt S: Shark cartilage and nutriceutical update. Alternative & Complementary Therapies 1: 414-416, 1995.

20. Anonymous: Therapy consultation: Shark cartilage for cancer treatment. American Journal of Health-System Pharmacy 52: 1756/1760, 1995.

21. Fontenele JB, Araujo 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. Biological and Pharmaceutical Bulletin 20(11): 1151-1154, 1997.

22. Harshbarger JC, Ostrander GK.: Cancer in sharks, skates, rays, and other lower fishes. Proceedings of the American Association for Cancer Research 41: A4848, 2000.

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

24. Wellings SR: Neoplasia and primitive vertebrate phylogeny: echinoderms, prevertebrates, and fishes--a review. National Cancer Institute Monograph 31: 59-128, 1969.

25. Durie BG, Soehnlen B, Prudden JF: Antitumor activity of bovine cartilage extract (Catrix-S) in the human tumor stem cell assay. Journal of Biological Response Modifiers 4(6): 590-595, 1985.

26. Murray JB, Allison K, Sudhalter J, et al.: Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. Journal of Biological Chemistry 261(9): 4154-4159, 1986.

27. Moses MA, Sudhalter J, Langer R: Identification of an inhibitor of neovascularization from cartilage. Science 248: 1408-1410, 1990.

28. Moses MA, Sudhalter J, Langer R: Isolation and characterization of an inhibitor of neovascularization from scapular chondrocytes. Journal of Cell Biology 119(2): 475-482, 1992.

29. Moses MA: A cartilage-derived inhibitor of neovascularization and metalloproteinases. Clinical and Experimental Rheumatology 11(suppl. 8): S67- S69, 1993.

30. Takigawa M, Pan H-O, Enomoto, et al.: A clonal human chondrosarcoma cell line produces an anti-angiogenic antitumor factor. Anticancer Research 10: 311-316, 1990.

31. Ohba Y, Goto Y, Kimura Y, et al.: Purification of an angiogenesis inhibitor from culture medium conditioned by a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8. Biochimica et Biophysica Acta 1245: 1-8, 1995.

32. Sadove AM, Kuettner KE: Inhibition of mammary carcinoma invasiveness with cartilage-derived inhibitor. Surgical Forum 28: 499-501, 1977.

33. Langer R, Brem H, Falterman K, et al.: Isolation of a cartilage factor that inhibits tumor neovascularization. Science 193: 70-71, 1976.

34. Langer R, Conn H, Vacanti J, et al.: Control of tumor growth in animals by infusion of an angiogenesis inhibitor. Proceedings of the National Academy of Sciences USA 77(7): 4331-4335, 1980.

35. Takigawa M, Shirai E, Enomoto M, et al.: Cartilage-derived anti-tumor factor (CATF) inhibits the proliferation of endothelial cells in culture. Cell Biology International Reports 9(7): 619-625, 1985.

36. Takigawa M, Shirai E, Enomoto M, et al.: A factor in conditioned medium of rabbit costal chondrocytes inhibits the proliferation of cultured endothelial cells and angiogenesis induced by B16 melanoma: its relation with cartilage-derived anti-tumor factor (CATF). Biochemistry International 14(2): 357-363, 1987.

37. Hiraki Y, Inoue H, Iyama K-I, et al.: Identification of chondromodulin I as a novel endothelial cell growth inhibitor. Journal of Biological Chemistry 272(51): 32419-32426, 1997.

38. Pauli BU, Memoli VA, Kuettner KE: Regulation of tumor invasion by cartilage-derived anti-invasion factor in vitro. Journal of the National Cancer Institute 67(1): 65-70, 1981.

39. Lee A, Langer R: Shark cartilage contains inhibitors of tumor angiogenesis. Science 221(4616): 1185-1187, 1983.

40. Davis PF, He Y, Furneaux RH, et al.: Inhibition of angiogenesis by oral ingestion of powdered shark cartilage in a rat model. Microvascular Research 54(2): 178-182, 1997.

41. Sheu JR, Fu CC, Tsai ML, et al.: Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities. Anticancer Research 18: 4435-4442, 1998.

42. McGuire TR, Kazakoff PW, Hoie EB, et al.: Antiproliferative activity of shark cartilage with and without tumor necrosis factor-a in human umbilical vein endothelium. Pharmacotherapy 16(2): 237-244, 1996.

43. Oikawa T, Ashino-Fuse H, Shimamura M, et al.: A novel angiogenic inhibitor derived from Japanese shark cartilage (I): extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis. Cancer Letters 51(3): 181-186, 1990.

44. Morris GM, Coderre JA, Micca PL, et al.: Boron neutron capture therapy of the rat 9L gliosarcoma: Evaluation of the effects of shark cartilage. British Journal of Radiology 73: 429-434, 2000.

45. Dupont E, Alaoui-Jamali M, Wang T, et al.: Angiostatic and antitumoral activity of AE-941 (Neovastat-R), a molecular fraction derived from shark cartilage. Proceedings of the American Association for Cancer Research 38: A1530, 1997.

46. Riviere M, Alaoui-Jamali M, Falardeau P, et al.: Neovastat: an inhibitor of angiogenesis with anti-cancer activity. Proceedings of the American Association for Cancer Research 39: A317, 1998.

47. Sirois MG: AE-941, a new and specific VEGF antagonist? Proceedings of the American Association for Cancer Research 40: A1517, 1999.

48. Liang JH, Wong KP: The characterization of angiogenesis inhibitor from shark cartilage. Advances in Experimental Medicine and Biology 476: 209-223, 2000.

49. Wojtowicz-Praga S: Clinical potential of matrix metalloproteinase inhibitors. Drugs R&D 1(2): 117-129, 1999.

50. Suzuki F: Cartilage-derived growth factor and antitumor factor: Past, present, and future studies. Biochemical and Biophysical Research Communications 259: 1-7, 1999.

51. PDQ Clinical Trials Database (URL: http://cancernet.nci.nih.gov): Phase III randomized study of induction chemotherapy and radiotherapy with or without AE-941, a shark cartilage extract, in patients with stage IIIA or IIIB unresectable non-small cell lung cancer. Protocol IDs: MDA-ID-99303, NCI-T99- 0046. Status: Active. Database accessed: July 10, 2000.

52. PDQ Clinical Trials Database (URL: http://cancernet.nci.nih.gov): Phase III randomized study of AE-941 (shark cartilage extract) in patients with metastatic renal cell carcinoma refractory to immunotherapy. Protocol IDs: AETERNA-AE-RC-99-02, CAN-CCI-ETH-00-32-17, CCF-IRB-3664, JGH-00023, UPCC- 2800. Status: Active. Database accessed: October 13, 2000.

53. Folkman J: The role of angiogenesis in tumor growth. Seminars in Cancer Biology 3: 65-71, 1992.

54. Sipos EP, Tamargo RJ, Weingart JD, et al.: Inhibition of tumor angiogenesis. Annals of the New York Academy of Sciences 732: 263-272, 1994.

55. Li C-Y, Shan S, Huang Q, et al.: Initial stages of tumor cell-induced angiogenesis: Evaluation via skin window chambers in rodent models. Journal of the National Cancer Institute 92(2): 143-147, 2000.

56. Alberts B, Bray D, Lewis J, et al.: The Molecular Biology of the Cell, Third Edition (Garland Publishing, New York, NY), 1294 pages, 1994.

57. 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. Journal of Molecular Medicine 76: 275-288, 1998.

58. Rosen J, Sherman WT, Prudden JF, et al.: Immunoregulatory effects of Catrix. Journal of Biological Response Modifiers 7(5): 498-512, 1988.

59. Houck JC, Jacob RA, DeAngelo L, et al.: The inhibition of inflammation and the acceleration of tissue repair by cartilage powder. Surgery 51: 632- 638, 1962.

60. Simone CB, Simone NL, Simone CB: Shark cartilage for cancer. Lancet 351: 9113, 1998.

61. Horsman MR, Alsner J, Overgaard J: The effect of shark cartilage extracts on the growth and metastatic spread of the SCVII carcinoma. Acta Oncologica 37: 441-445, 1998.

62. Moses MA: The regulation of neovascularization by matrix metalloproteinases and their inhibitors. Stem Cells 15: 180-189, 1997.

63. Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. Journal of Clinical Investigation 103(9): 1237-1241, 1999.

64. Haas TL, Madri JA: Extracellular matrix-driven metalloproteinase production in endothelial cells: Implications for angiogenesis. Trends in Cardiovascular Medicine 9(3/4): 70-77, 1999.

65. McCawley LJ, Matrisian LM: Matrix metalloproteinases: Multifunctional contributors to tumor progression. Molecular Medicine Today 6: 149-156, 2000.

66. Pettit GR, Ode RH: Antineoplastic agents L: isolation and characterization of sphyrnastatins 1 and 2 from the hammerhead shark Sphyrna lewini. Journal of Pharmaceutical Sciences 66(5): 757-758, 1977.

67. Sigel MM, Fugman RA: Studies on immunoglobulins reactive with tumor cells and antigens. Cancer Research 28: 1457-1459, 1968.

68. Snodgrass MJ, Burke JD, Meetz, GD: Inhibitory effect of shark serum on the Lewis lung carcinoma. Journal of the National Cancer Institute 56(5): 981-983, 1976.

69. Pugliese PT, Heinerman J: Devour Disease with Shark Liver Oil (Impakt Communications, Green Bay, WI), 63 pages, 1999.

70. Berberi P, Thibodeau A, Germain L, et al.: Antiangiogenic effects of the oral administration of liquid cartilage extract in humans. Journal of Surgical Research 87: 108-113, 1999.

71. Ashar B, Vargo E: Shark cartilage-induced hepatitis. Annals of Internal Medicine 125(9): 780-781, 1996.



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