[MOL] Info. on Topetocan/suzanne [02755] Medicine On Line

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[MOL] Info. on Topetocan/suzanne

Hope this is informative, Love Mam

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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

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

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. 

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