NEWS

Natural Compounds Show Antiangiogenic Activity

Charles Marwick

Ever since evidence emerged that growth of malignant tumors could be slowed or even prevented by cutting off their blood supply, the search for antiangiogenic agents has widened and now includes natural compounds and compounds derived from natural agents.

"There are easily 4 dozen natural compounds that are antiangiogenic," said Raymond Chang, M.D., medical director of Meridian Medical Group, New York, and clinical assistant professor of medicine at the Albert Einstein School of Medicine, N.Y. "The field is complex and it’s important to realize this. There is no magic bullet here. There is no single answer, no single pathway," he warned.

At the recent fourth annual conference on Integrating Complementary and Alternative Therapies in Cancer in Arlington, Va., Chang reviewed a number of studies involving various natural compounds and extracts of natural compounds that have shown some antiangiogenic activity.

They include shark cartilage, curcumin (the yellow pigment in tumeric), the omega-3 and omega-6 fatty acids, green tea, licorice, quercetin (a bioflavonoid present in fruits and vegetables), squalamine (an extract of dogfish liver), and vitamin D3.

Some of these agents are in clinical trials. For instance, one form of shark cartilage extract, Neovastat, is being developed by Aeterna Laboratories, Quebec, Canada. It is in early phase III trials for the management of renal cell carcinoma, non-small-cell lung cancer, and prostate cancer. Another agent is squalamine, which is in phase II trials, sponsored by Genaera Laboratories, Plymouth Meeting, Pa., for the treatment of some solid tumors and lung and ovarian cancers.

Multiple Processes

Chang pointed out that there are multiple processes at work in angiogenesis: gene expression, enzyme activity, and signal processing. This, he suggested, may be one of the problems with trials of these agents in attempting to control tumor growth. "They don’t act in any single modality. They may be antiangiogenic but they have other properties as well," said Chang.

Another problem he cited is the lack of agreement on the assays for studying the effects of these agents. He noted that there are many assays for antiangiogenesis, but they have varying degrees of sensitivity and are not always appropriate for testing a particular agent.

Most of the studies of antiangiogenic activity are based on in vitro or animal work, which cannot be readily extrapolated to humans. There are only preclinical data for most of the naturally derived antiangiogenic agents, and "none so far have shown any dramatic results," Chang said.

Given the multiple effects of these agents, Chang said that the future of their use in managing cancer lies in combinations. He suggested using some of these natural agents along with current standard anticancer treatment modalities such as chemotherapy and radiation, and he noted that some studies of this approach are under way.

The natural antiangiogenic agents themselves might also be used in combination, in what he called an "optimal antiangiogenic cocktail." Arguing that there is a synergistic effect from the use of multiple agents with different antiangiogenic activities, Chang suggests that it is reasonable and logical to combine them. "Ultimately that is what will happen," he predicted.

Financial Incentive

A familiar issue in studying natural compounds that may have value in therapeutic medicine is that they are not patentable and thus not financially attractive agents for drug development and for mounting the necessary clinical trials. There are exceptions. For example, the process of extracting the shark cartilage that is the active material in Neovastat has been patented. This issue is addressed in a forthcoming report from the White House Commission on Complementary and Alternative Medicine Policy.

The Commission’s report, to appear in March 2002, is still in the draft stage, but the chair of the Commission, James S. Gordon, M.D., of Georgetown University School of Medicine, Washington, D.C., gave the Arlington meeting an advance look at some of the topics the Commission is addressing. Adequate funding for studies of natural products is one recommendation.



             
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