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Chemist Improves Synthesis of Scarce Drugs

By Michael Vatalaro

A Nobel Prize-winning chemist has devised a simpler and more effective method of synthesis for two experimental anticancer drugs, each 100 times more powerful than Taxol. The new process could allow the previously scarce compounds to become widely available treatment options if they are proven effective in clinical trials and approved by the Food and Drug Administration.

Dr. Elias J. Corey, a professor of chemistry at Harvard University and winner of the 1990 Nobel Prize in chemistry, and Eduardo J. Martinez, a predoctoral student in Corey's lab, improved the original synthesis of ecteinascidin, a potent antitumor agent discovered in 1988. Until recently, the compound was not widely available; it had to be purified from its natural source, where it exists in tiny quantities.

Now, with the new, highly efficient method of synthesis, it is possible to produce ecteinascidin and a related drug, phthalascidin, commercially. "The number of lives [the drugs] will save will not be limited by supply," said Corey. The new method was reported in the April issue of Organic Letters, a publication of the American Chemical Society.

Ecteinascidin has shown the ability to shrink drug-resistant soft tissue sarcomas — tumors of the muscles, tendons and supportive tissues. Approximately 10,000 Americans each year develop soft tissue sarcomas, which typically are treated with surgery and radiation. Chemotherapy is not a first-line treatment in many forms of the cancer. As many as 40 percent of sarcoma patients who do receive chemotherapy experience a short remission followed by the return of the tumor — now impervious to chemotherapy. Clinicians are concentrating their testing of ecteinascidin on these drug-resistant tumors.

Preliminary results from phase 2 clinical trials indicated that tumors stopped growing or shrank in 47 percent of patients (14 of 30) given ecteinascidin. The results were announced in May at the American Society of Clinical Oncology meeting in New Orleans.

Both ecteinascidin and phthalascidin show remarkable antitumor activities, killing living tumor cell lines in the lab with an efficiency roughly two orders of magnitude greater than that of Taxol, a leading anticancer drug. Isolated from a marine organism collected in the Caribbean by Dr. Ken Rinehart, a professor of chemistry at the University of Illinois, Urbana-Champaign, ecteinascidin soon was found to show dramatic levels of anticancer activity, even at miniscule doses. Until 1996, the only source of the drug was a small reef-dwelling tunicate called Ecteinascidia turbinata found in the West Indies (see photo). Researchers had to harvest over 1 ton of these sea squirts to produce 1 gram of ecteinascidin. In 1996, Corey and his collaborator Dr. David Gin, now at the University of Illinois, published the first successful chemical synthesis of the molecule. This synthesis offered hope that the production of ecteinascidin could be done independent of the natural source. Both Corey and Rinehart are long-time grantees of NIGMS, having received a combined 63 years of support.

A cluster of Ecteinascidia turbinata, the tunicate from which the drug ecteinascidin is purified. Photo courtesy of PharmaMar

PharmaMar, a Spanish pharmaceutical company, bought the rights to the compound and began harvesting the tunicate to produce it. Currently, PharmaMar grows Ecteinascidia in an aquaculture facility in Spain, a more practical and environmentally sound practice than harvesting the creature from the wild. The new synthesis, which has fewer steps and is more efficient overall, may make raising Ecteinascidia in tanks unnecessary, as it potentially enables the production of the drug in lots measured in kilograms instead of grams. Since each patient treated receives just 4.5 milligrams of ecteinascidin over a 3-week period, Corey estimates that 5 kilograms of the drug could supply the world's research and clinical needs for the next few years.

Recent research indicates that ecteinascidin may even be able to prevent tumors from becoming drug-resistant in the first place. According to a study conducted by Dr. Kathleen Scotto at Memorial Sloan-Kettering Cancer Center in New York City, ecteinascidin prevents the formation of P-glycoprotein, a protein associated with multidrug-resistant tumors. P-glycoprotein is a membrane protein that transports toxins such as chemotherapy agents out of cancer cells, preventing the chemotherapy drugs from destroying the tumor. Previous studies by Scotto's lab have indicated that when some tumors are exposed to chemotherapy agents, they quickly boost the activity of the MDR1 gene, which is responsible for the formation of P-glycoprotein. By interfering with that process, ecteinascidin may keep the tumor cells vulnerable to chemotherapy. Even if ecteinascidin is not proven effective on its own, it may become a key ingredient in chemotherapy "cocktails" to prevent tumors from developing resistance to drugs currently in use. The work was published in the Proceedings of the National Academy of Sciences in June and supported in part by the National Cancer Institute.

Phthalascidin, which is a derivative of the natural compound, was developed in Corey's lab. It is not being tested in humans at this time although its simpler structure and synthesis give it even greater potential as a drug. "This type of research is driven by the great power of modern chemistry. I hope that ecteinascidin and phthalascidin will be useful as life-saving drugs, but it will be another 5 years before we know for certain," said Corey.

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