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Wistar Scientists Define Mechanism Of Action Used By Potential Magic Bullet In Cancer Treatment

Farnesyltransferase inhibitors (FTIs) are a relatively new class of nontoxic chemotherapeutic drugs that have an ability to target mutated oncogenes while bypassing normal cells; i.e., they may be the long sought-after magic bullet in cancer treatment.

In pre-clinical studies, FTIs have proven to control the growth of cancer cells and promote tumor regression. Little has been known, however, about how and why they work.

From their recent studies of FTIs, Wistar scientist, George Prendergast, Ph.D., and his Wistar research team made some surprising discoveries about their mechanism of action. Their findings appear today in the March issue of the scientific journal, Molecular and Cellular Biology.

The Wistar scientists had expected FTIs to interfere in some way with the activity of RAS, a cancer protein that tells cells when to start and stop dividing. Instead, they found that FTIs act in large part by affecting RHO, a class of proteins that regulate cell shape, survival and motility. Since RHO levels are elevated in many metastatic tumors, scientists have suspected for some time that RHO and cancer are in some way related. They had not known, however, if their relationship was causative or correlative.

One significant and unexpected finding of the study was that FTIs activate features of RHO by stimulating the production of an isoform with altered properties in the cell. In this way, FTIs make it possible for RHO to perform activities it could not previously perform.

An understanding of RHO alteration as the tumor principle targeted by FTIs will make it possible to make FTIs more effective, avoid drug resistance problems, and design other types of nontoxic antitumor drugs that target the same principle.


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Contact: Diana Cutshall
dcutshall@wistar.upenn.edu
215-898-3716
The Wistar Institute
17-Feb-1999


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