According to the National Cancer Institute, in the year 2000, approximately 8,100 Americans will develop soft tissue sarcomas--tumors of the muscles, tendons, and supportive tissues. These cancers typically require surgery and radiation treatment. Chemotherapy is not a frontline treatment for most soft-tissue sarcomas because up to 40 percent of those who are treated with chemotherapy agents experience a relapse of the cancer. Worse still, the returning cancer is often impervious to the chemotherapy drugs.
Dr. Elias J. Corey at Harvard University, the 1990 Nobel laureate in chemistry, may change that. He has improved the synthesis of ecteinascidin, a potent antitumor agent roughly 100 times more powerful than Taxol , a leading anticancer drug. Although ecteinascidin was discovered in 1988, it has not been widely available because it had to be purified from its natural source, where it exists in tiny quantities. Dr. Corey's new synthesis makes commercial-scale production possible. Ecteinascidin is in Phase II clinical trials and has shown the ability to shrink drug-resistant soft tissue sarcomas. In addition, it may inhibit drug resistance in other forms of cancer. Other researchers have shown that ecteinascidin prevents the formation of P-glycoprotein, a protein associated with multidrug-resistant tumors. P-glycoprotein transports toxins such as chemotherapy drugs out of cancer cells, thereby preventing the drugs from destroying the tumor. Ecteinascidin stops cells from forming more P-glycoprotein, eliminating one of the cancer cells' best defenses against chemotherapy agents. If its clinical trials are successful and it is eventually approved by the U.S. Food and Drug Administration, ecteinascidin would be the only drug available to treat those sarcoma patients in whom a prior round of chemotherapy had failed. Additionally, by preventing the formation of P-glycoprotein, ecteinascidin may keep other types of tumor cells vulnerable to chemotherapy. Even if ecteinascidin is not proven to be effective on its own, it may become a key ingredient in chemotherapy "cocktails" to prevent tumors from developing resistance to existing anticancer drugs.
Martinez EJ and Corey EJ. A new, more efficient and effective process for the synthesis of a key pentacyclic intermediate for production of ecteinascidin and phthalascidin antitumor agents. Org. Lett. 2000;2:1097-100.
Jin S, Gorfajn B, Faircloth G and Scotto KW. Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation. Proc. Natl. Acad. Sci. USA 2000;97:6775-9.
Reporters may call the NIGMS Office of Communications and Public Liaison at (301) 496-7301 to obtain the name of a scientist in the NIGMS Division of Pharmacology, Physiology, and Biological Chemistry who can comment on this work.
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12/4/2018 4:09 PM
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