If this is not your name, click here.
| | If this is not your name, click here. | | |
| | Contact Us | Order Now | Journals | Bookstore | Register a colleague | | |
| |  Topotecan Anti-Cancer Drug Approved by FDA WASHINGTON, May 29, 1996 -- The Food and Drug Administration (FDA) has approved Topotecan , the first of a new class of drugs to treat patients whose advanced ovarian cancers have not responded favorably to standard treatments. SmithKline Beecham, works by interfering with an enzyme, topoisomerase I, that uncoils DNA before cell division by creating and resealing nicks in the DNA. Altered function of the enzyme eventually leads to tumor cell death. "The approval of Topotecan is significant because it is the first of a series of drugs with a new mechanism of action, which opens the door to the development of unique methods of treatment," said Edward Sausville, M.D., associate director of the National Cancer Institute's (NCI) Developmental Therapeutics Program. "This approval re-emphasizes the importance of natural products and their derivatives in the search for better cancer treatments." Topotecan, to be marketed as Hycamtin by SmithKline Beecham Pharmaceuticals, is derived from the bark of a Chinese tree known scientifically as Camptotheca acuminata. In 1958 Monroe Wall, Ph.D., then at the Department of Agriculture, and the late Jonathan Hartwell, M.D., of NCI discovered the antitumor activity of extracts from this plant in the course of a screening project for a natural source of steroids to make cortisone. In 1966, with the support of NCI's Natural Products Branch, Wall and Mansukh Wani, Ph.D., successfully isolated the active ingredient, camptothecin, from bark extracts. Clinical trials using a soluble salt of camptothecin began in the early 1970s, but the drug proved too toxic for clinical use. Following these discouraging results, camptothecin research continued slowly, and efforts focused on discovering how the drug killed cells. Still hoping to harness the antitumor activity in a better-tolerated chemical form, NCI funded research to find less toxic derivatives of the compound. By the early 1980s, scientists at NCI and other institutions had discovered that camptothecin caused DNA and RNA damage, which eventually led to tumor cell death. Scientists at SmithKline then approached Johns Hopkins University researchers and in parallel trials, both teams tested camptothecin samples from the NCI, for their ability to inhibit a second topoisomerase enzyme, topoisomerase II, an enzyme present in all cells at a constant level. Johns Hopkins' scientists were conducting research on topoisomerase II inhibitors, and camptothecin shared similar properties with many of the known topoisomerase II blockers. It was found, however, that camptothecin strongly inhibited topoisomerase I, rather than topoisomerase II. This discovery was important because the drug -- based on the presence of the enzyme in high levels in tumor cells -- might be more selective for tumor cells. Efforts to modify camptothecin for clinical use were quickly renewed, and scientists belonging to a National Cooperative Drug Discovery Group (NCDDG), sponsored and coordinated by the NCI, were able to successfully alter camptothecin. By 1990, Topotecan had been semi-synthesized by SmithKline Beecham, the industrial partner in the NCDDG. In addition, several other modified camptothecins, such as irinotecan, had been synthesized by research teams at NCI and other institutions. Topoisomerase I, the target enzyme of these new agents, exists in both normal and tumor cells and appears to take advantage of the growth rate difference between them. Researchers are not sure why, but there are two possible explanations. Topoisomerase I is most vulnerable in cells at a stage of the cell cycle known as the "S" phase. In this phase, cells copy their DNA while preparing to divide; therefore, the target enzyme is present more frequently and at a higher concentration. Since rapidly-proliferating tumors have a greater percent of cells in "S" phase, compared to normal, slow-growing cells, tumors are more susceptible to the action of Topotecan. A second explanation might be that rapid metabolic processes of tumor cells enable greater influx of the drug. Whatever the mechanism, Topotecan has had positive trial results. In a series of clinical trials supported jointly by NCI and SmithKline Beecham , the compound showed activity against a variety of solid tumors including ovarian cancer, small-cell lung cancer, and others. In trials conducted in Europe by the European Organization for the Research and Treatment of Cancer, Topotecan was shown to have similar anti-tumor activity against a variety of tumor types. In later Phase III trials, examining Topotecan as second-line therapy against ovarian cancers, response rates were 10 percent to 15 percent among patients who had not previously responded to standard treatment and 25 percent to 30 percent among patients who had responded to first-line therapy. In one study, comparing Topotecan and taxol for the treatment of advanced, recurrent ovarian cancer, Topotecan showed a 20 percent response rate, whereas taxol had a 12 percent response rate. According to some researchers, Topotecan is as significant as taxol in terms of a unique mechanism of action and novelty of approach. Response rates as high as 39 percent also have been seen in Phase III trials using the drug as a first-line treatment for small-cell lung cancer. Future studies will look at how Topotecan performs when used in combination with other drugs, such as cisplatin. The Cancer Information Service (CIS), a program of the National Cancer Institute, provides a nationwide telephone service for cancer patients and their families, the public, and health care professionals. CIS information specialists have extensive training in providing up-to- date and understandable information about cancer and cancer research. They can answer questions in English and Spanish and can send printed material. In addition, CIS offices serve specific geographic areas and have information about cancer-related services and resources in their region. The toll-free number of the CIS is 1-800-4-CANCER (1-800-422-6237). People with TTY equipment may call 1-800-332-8615. This document is also available through the NCI's CancerFax and CancerNet services, and in the News Section of the PDQ database. To get the document from CancerFax, dial 301-402-5874 from the handset of your fax machine and follow the recorded instructions to receive the contents list. Individuals who have access to the Internet may access the document on CancerNet, through an electronic mail (E-mail) service or via the National Institutes of Health (NIH) gopher. To get the CancerNet contents list from the E-mail service, send an E-mail message that says "help" in the body of the message to cancernet@icicc.nci.nih.gov. To get the document from CancerNet via the NIH gopher, point your gopher client to gopher.nih.gov and look for CancerNet under "Health and Clinical Information." To get the document from NCI's PDQ database, access PDQ News on the National Library of Medicine's MEDLARS system or consult a medical librarian for assistance. Additional information on this and other research topics may be found on the home page of the NCI's International Cancer Information Center's World Wide Web server located at http://wwwicic.nci.nih.gov.
|
