THE POTENTIAL OF FARNESYLTRANSFERASE INHIBITORS AS CANCER CHEMOTHERAPEUTICS

Mutant ras oncogenes and alterations in the mitogenic signaling pathwa ys that they regulate are associated with a wide variety of solid tumo rs and leukemias for which existing chemotherapeutics have limited uti lity. Of the possible approaches to inhibit Ras function, much attenti on has focused on a posttranslational modification, farnesylation, whi ch is required for the subcellular localization of Ras to the plasma m embrane and is critical to Ras cell-transforming activity. Inhibitors of the enzyme that catalyzes Ras farnesylation, farnesyl-protein trans ferase (FPTase), have been developed. These compounds inhibit the tumo rigenic phenotypes of ras-transformed cells and human tumor cells in c ell culture and in animal models. Moreover, FPTase inhibitors have not demonstrated toxicity to normal cells in culture or to normal tissues in mice. FPTase inhibitors are among the first small molecule compoun ds designed from studies of oncogenes that might serve as novel cancer chemotherapeutics.