By Penny Stern, MD

NEW YORK, Apr 13, 2000 (Reuters Health) -- In the battle against cancer, drug therapy can be a key weapon. In a new report, Nobel Prize-winning chemist Dr. Elias J. Corey and graduate student Eduardo Martinez of Harvard University, announce their successful development of a synthetic process to produce two powerful drugs, ecteinascidin and phthalascidin, compounds that may eventually augment our arsenal of cancer-fighting drugs.

"Our new process... represents a tremendous improvement in the process of making either (drug)," Corey told Reuters Health. Corey won the Nobel Prize for chemistry in 1990 for his work in organic chemistry.

In the interview, he explained the origins of these drugs. "Ecteinascidin was discovered by Professor Kenneth Rinehart at the University of Illinois as a natural product found in trace amounts in (a) reef-dwelling marine organism," he said. This sea creature normally inhabits the reefs of the West Indies.

Because ecteinascidin could only be obtained in very limited quantities, it was difficult to fully explore the substance's properties. What was clear, however, was that ecteinascidin "was a very, very potent anti-tumor agent," Corey continued.

Dr. David Gin, working with Corey, developed the first synthetic process for ecteinascidin in 1996. This method, patented by Harvard University and licensed to PharmaMar, a Spanish biotech company that focuses on developing therapeutic agents from marine sources, has allowed "commercial-scale synthesis" of the compound, according to Corey. But when large-scale synthesis was pursued, snags were found in the process.

"Our new synthesis overcomes these troublesome steps," Corey says. As these problems were being resolved in the laboratory, Corey and Martinez "designed another drug, roughly of the same class but of a different chemical structure, which we call phthalascidin," Corey related.

This synthesis was reported in the Proceedings of the National Academy of Sciences in March 1999 by Corey, Martinez, and Harvard colleagues.

While phthalascidin bears some similarities to ecteinascidin -- and seems equally as potent -- "it's easier to make and promises to have certain advantages," the researcher said.

Writing in the April 6th issue of Organic Letters, a publication of the American Chemical Society, the Cambridge, Massachusetts-based team points out that their synthetic process also results "in excellent yield" of phthalascidin. For these reasons, phthalascidin "may prove to be a more practical therapeutic agent" than even ecteinascidin, the investigators suggest.

Ecteiniscidin is currently being tested in humans. According to Corey, "the most exciting thing that has emerged so far is the (drug's) effectiveness against sarcoma." Sarcoma are tumors that arise from a variety of tissues, such as muscle and lymph. They are notoriously difficult to treat and in fact, "there is (virtually) no effective drug treatment for sarcoma," Corey noted.

He believes that the drug's unique mechanism of action may explain why it is effective against sarcoma. "The drug has a different mechanism of action from every one of the chemotherapeutic agents now used and the way we know this, is that... tumor (cells) that have developed resistance to known and standard chemotherapeutic agents... are still sensitive to ecteinascidin or phthalascidin," Corey said.

"We are now studying this mechanism of action and if we can identify the target protein that the drug attacks," he noted, "we're on the way to looking at a range of other chemical structures that could also attack that protein, or block that target protein."

Asked when the drug might come to market, Corey said that the current trials "are scheduled to be wound up at the end of this year." At that point, PharmaMar plans to apply to the US Food and Drug Administration for fast-track approval so that means 6 more months of studies, he added. "It's hoped that within 6 months, there will be a definitive answer as to whether these patients are benefited by ecteinascidin 743." It is possible that the drug could be available in 2002.

Though Corey stressed that it is "early" yet to judge how the drug will perform in terminally ill patients, "there's hope where there was none." SOURCE: Organic Letters 2000;2:993-996; Proceedings of the National Academy of Sciences 1999;96:3496-3501.

reprinted from: http://dailynews.yahoo.com/h/nm/20000413/hl/dgb_39.html