FARNESYL TRANSFERASE INHIBITORS CAUSE ENHANCED MITOTIC SENSITIVITY TOTAXOL AND EPOTHILONES

An important class of cellular proteins, which includes members of the p21ras family, undergoes posttranslational farnesylation, a modificat ion required for their partition to membranes. Specific farnesyl trans ferase inhibitors (FTIs) have been developed that selectively inhibit the processing of these proteins. FTIs have been shown to be potent in hibitors of tumor cell growth in cell culture and in murine models and at doses that cause little toxicity to the animal. These data suggest that these drugs might be useful therapeutic agents. We now report th at, when FTI is combined with some cytotoxic antineoplastic drugs, the effects on tumor cells are additive. No interference is noted. Furthe rmore, FTI and agents that prevent microtubule depolymerization, such as taxol or epothilones, act synergistically to inhibit cell growth. F TI causes increased sensitivity to induction of metaphase block by the se agents, suggesting that a farnesylated protein may regulate the mit otic check point. The findings imply that FTI may be a useful agent fo r the treatment of tumors with wild-type ras that are sensitive to tax anes.