Shark Cartilage: Anticancer Agent or Hype?US Pharmacist June 1998 Shark Cartilage: Anticancer Agent or Hype? Stephen J. Cutler, Ph.D., Assistant Professor Amy S. Henson, Pharm.D. (cand.) Selena S. Ready, Pharm.D. (cand.) >Natural Products Discovery Group, Department of Pharmaceutical Sciences, School of Pharmacy, Mercer University Atlanta, GA The ability of an unidentified agent in shark cartilage to inhibit angiogenesis has consumers willing to test its anticancer potential. Shark cartilage has received considerable attention among consumers and healthcare professionals for its cancer-fighting potential. A recent study indicated that 25,000 people a year buy shark cartilage in the form of pills and powders at health-food stores.<1> The substances popularity is due in part to the belief that a protein found in the cartilage has the ability to inhibit angiogenesis, which is needed to provide nutrients for tumor growth and cancer metastasis.<2,3> Cancer is the second leading cause of death in the United States, claiming more than 500,000 lives each year.<4> Therefore, many consumers are willing to explore alternatives, such as shark cartilage, in order to decrease their chances of developing this disease. Many healthcare professionals are skeptical about shark cartilage. They are concerned that cancer patients will stop complying with traditional treatment in favor of such alternative treatments -- the efficacy of which is less well-substantiated. Those ministering to cancer patients need to be aware of the relevant facts regarding shark cartilage and its role in cancer prevention and therapy. By educating themselves, healthcare providers can help patients make an informed decision about choosing shark cartilage therapy. Neoplasms Rare in Sharks The cancer rate for sharks is estimated to be one in one million or less.<4> This rarity of neoplasms in these animals has led researchers to ask whether sharks contain a biochemical that deters the development of many common types of cancer. Sharks are among the most primitive of living vertebrates, seemingly untouched by the forces of evolution. They have survived largely unchanged for millions of years.<5> Unlike humans, their skeletal structure is composed entirely of cartilage, which constitutes 6% - 8% of their gross weight.<6> This abundance of cartilage may explain why cancer in sharks is rare compared to cancer in other fish species. Cartilage contains a substance that strongly inhibits the growth of new blood vessels toward solid tumors. Mammals have less inhibiting factor due to a lower amount of cartilage (~1%) per body weight.<6> Angiogenesis and Tumor Growth Solid tumors may arise for any number of reasons. Tumor growth rates and metastasis are unique, depending on the type and location of cancer. The physiology and pathology associated with the development of malignant tumors is less of a mystery. Malignant tumors continue to grow new blood vessels in order to obtain oxygen and nutrients for growth.<7> In the early 1970s, tumors were found to secrete tumor angiogenesis factor (TAF), which stimulates existing blood vessels to branch and grow.<8> Once the blood supply of normal organs is established, it is relatively stable, but the growth and development of a tumor's blood supply are constantly changing to meet the tumor's needs. As a result, inhibiting the recruitment of new vessels may diminish tumor growth and development.<9> The process of tumor metastasis is complex and may be broken down into a number of associated steps. First, there is angiogenesis, which involves the formation of a blood supply. At this stage, the endothelial cells at the tip of the vessels elongate toward the tumor. This is followed by a second phase, wherein the endothelial cells are initiated to proliferate. This proliferation expands in the direction of the tumor until the tumor is reached. These points in the initiation stage are vulnerable to certain types of antineoplastic agents. In 1973, Judah Folkman and colleagues at Children's Hospital Medical Center in Boston implanted a few cancer cells in the cornea of rabbits' eyes and observed new vascularization in as little as seven days.<8> Upon implantation of cartilage (which is not normally vascularized) into the corneas, the researchers noted that the tumor was not invaded by new blood vessels. This study, paralleling others, allowed researchers to pinpoint the actual activity of the factor found in cartilage and demonstrate that the process of cell proliferation in angiogenesis was inhibited.<10> A vulnerable link in the carcinogenic pathway had been found using this antiangiogenic factor. Robert Langer, Ph.D., of Massachusetts Institute of Technology, has shown that shark cartilage contains 1,000 times more of the angiogenesis inhibitors than does cartilage from any other animal studied. In a 1983 study using basking sharks (Cetorhinus maximus), Lee and Langer found that the extract of the cartilage significantly inhibited tumor neovascularization. Collagenase is required for neovascularization; presumably, the inhibition of this key enzyme contributed to the antiangiogenic activity of the cartilage. Their experiments demonstrated that the extracts inhibited in vitro capillary growth by V2 carcinomas, as well as reduced the growth of V2 tumors in rabbit corneas compared to controls.<11> In 1996, another study using human umbilical vein endothelium demonstrated that shark cartilage at a concentration of 500 µg/mL reduced endothelial cell proliferation by 32%.<10> The single most limiting factor for further studies of cartilage is the lack of supply. Active Agent Proves Elusive While evidence shows that shark cartilage contains an agent that inhibits angiogenesis, the question remains: what makes this inhibition selective to cancerous growths? Many researchers believe that the answer lies in the fact that tumors send out blood vessels that grow in corkscrew fashion, while healthy tissues create blood vessels that grow in a linear direction. This difference allows the active product in cartilage to selectively inhibit tumor angiogenesis while permitting healthy host tissue to grow the necessary blood vessels.<12> However, research in this area is very limited, and further investigation must be done in order to corroborate this theory. Carefully controlled, replicated studies in humans are needed to fully evaluate the clinical usefulness of the active agent in the treatment of cancer. Primarily because the active natural product(s) has/have not been identified, the clinical application of shark cartilage cannot be quantified at this point. Over the last 20 years, researchers have attempted to isolate, purify and then synthesize the product (presumably a protein) responsible for the antiangiogenic activity. If the active ingredient is in fact a protein, some of it would have to be absorbed intact from the gastrointestinal tract in order to exert an effect. This poses a problem, because most proteins are easily digested in the gastrointestinal tract. One advantage that shark cartilage may possess is that the proposed active component may have a much lower molecular weight (10 daltons),<7> which may allow for gastrointestinal absorption of the angiogenesis inhibitor. However, isolating the angiogenesis-inhibiting protein would most likely involve separating it from a larger protein in which it is inserted or linked. This isolation process may render the protein less effective. In addition to the challenges of absorption and isolation, developing a method to dry and pulverize the cartilage without rendering the protein fibers ineffective presents another obstacle. This is largely due to the high water content of cartilage (85%) and the manner in which it is bound, which makes drying very difficult.<6> Advising Patients Food Supplement: Because shark cartilage is classified not as a drug but as a food supplement, pharmacists may not have readily available the information necessary to advise patients on its use. According to the FDA, a "food supplement" is something that is added to a food or diet. Examples of food supplements include vitamins, minerals, fiber, garlic, and unsaturated fish oils.<12> Food supplements are not considered medicinal and are not permitted to carry medical claims. They are controlled by the FDA's food regulations, but not by its drug regulations. As is the case with vitamins and minerals, production of shark cartilage must meet the FDA's guidelines for cleanliness, safety and labeling, but there is no standardization among products. As a consequence, there may be variations among batches depending upon the manufacturer and the sources of cartilage Indications and Efficacy: Indications for the use of shark cartilage include cancer, arthritis and angiogenesis-dependent diseases. Although not scientifically proven, other benefits may include advances in cataract surgery and new treatments for heart failure and hypertension.<13> For consumers choosing to use shark cartilage to treat cancer, pharmacists should first counsel the patient, pointing out the limited amount of scientific research conducted to date on the use of cartilage in controlling neoplastic growth. Recommended Intake: With this in mind, a conservative recommendation for adults is approximately 7 - 10 grams of shark cartilage per day to eliminate the development of new vessels. The regimen should be divided into three doses per day, taken approximately 15 minutes before meals to facilitate absorption. This regimen is derived from the amount of extract used in the limited studies involving in vitro and in vivo assays.<7,9-12 > Side Effects: Consumers should be informed about the possibility of as yet unknown side effects associated with prolonged inhibition of vessel growth. Delayed wound healing and contraception may be among the detectable side effects of therapy.<6> Contraindications: Contraindications should also be considered. For instance, individuals who need vascularization to occur should only use shark cartilage if so advised by their physician. For example, recent heart attack victims need to replace blood vessels in damaged tissue. In pregnancy, women are building a network of blood vessels to feed the embryo. Women who are attempting to conceive also should avoid shark cartilage, which may interfere with vascularization during the menstrual cycle. Those involved in a major muscle-building program and children also should avoid consuming shark cartilage. Conclusion Although angiogenesis and its effects on tumors have been well known for more than 20 years, only a handful of practitioners of alternative and complementary therapies employ shark cartilage to treat cancer patients. Surgery, chemotherapy and radiation remain the most commonly used treatments. Two facts remain constant: 1) cancer is the second leading cause of death in the United States, and 2) shark cartilage contains an antiangiogenic factor shown to slow cancer progression.<7,9-12> However, further controlled studies in humans are needed to substantiate the role of shark cartilage in the treatment of cancer. As research continues, shark cartilage may indeed prove to be significant in preventing and conquering cancer. REFERENCES Green S. Shark cartilage therapy against cancer. Nutrition Health Forum 1997;14:1-5. Hunt TJ, Connelly JF. Shark cartilage for cancer treatment. Am J Health-Syst Pharm. 1995;52:1756,1760. Mathews J. Media feeds frenzy over shark cartilage as cancer treatment. J Nat Cancer Inst, 1993;85:1190- 91. Gromlry James J. Cartilage: Providing new hope for cancer and other diseases. Better Nutrition 96;58:69,70. Kugler HJ. From shark immunity to improved human immunity. Total Health 1996;18:53. Lane WI, Comas L. Sharks Don't Get Cancer: How Shark Cartilage Could Save Your Life. I. William Lane, Linda Comas, eds. Garden City Park, NY: Avery Publishing Group Inc.; 1992. McGuire TR, Kazakoff PW, et al. Antiproliferative activity of shark cartilage with and without tumor necrosis factor alpha in human umbilical vein endothelium. Pharmacotherapy. 1996;(2):237-244. Maugh II TH. Angiogenesis inhibitors link many diseases. Science 1981;212:1374-75. Oikawa T, Ashina-Fuse H, Shimamaura M, et al. A novel abiogenic inhibitor derived from Japanese shark cartilage. Extraction and estimation of inhibitory activities toward tumor embryonic angiogenesis. Cancer Letters 1990;51:181-186. Langer R, Moses MA, Sudhatter J. Identification of an inhibitor of neovasculatization from cartilage. Science 1990;248:1408-10. Langer R, Lee A. Shark cartilage contains inhibitors of tumor angiogenesis. Science 1983;221:1185-7. Scheer JF. Shark Cartilage: A great attacker of cancer. Better Nutrition. 1996;58:60-65. Fox A, Taylor N. The wonders of shark cartilage. Let's Live. 1994;62(3):14-18.
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