Clinical activity of farnesyl transferase inhibitors in hematologic malignancies: Possible mechanisms of action

Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FTase). Initially developed to inhibit the prenylation necessary for Ras activation, their mechanism of action seems to be more complex, involving other proteins unrelated to Ras. FTIs have been developed and tested across a wide range of human cancers. At least 3 agents within this family have been investigated in hematologic malignancies. These are tipifarnib (R115777, Zarnestra(R)), lonafarnib (SCH66336, Sarasar(TM)), both of which are orally administered, and BMS-214662, which is given intravenously. Preliminary results from clinical trials demonstrate enzyme target inhibition, a favorable toxicity pro. le and promising efficacy. Ongoing studies will better determine their mechanism of action and the role of combination with other agents, de. ning their place in the therapeutic arsenal of hematologic disorders.