Development of the farnesyltransferase inhibitor tipifarnib for therapy of hematologic malignancies.
Farnesyltransferase inhibitors (FTIs) represent a new class of signal transduction inhibitors that block the processing of cellular polypeptides that have cysteine terminal residues and, by doing so, interdict multiple pathways involved in proliferation and survival of diverse malignant cell types. Tipifarnib is an orally bioavailable, nonpeptidomimetic methylquinolone FTI that is being tested clinically in diverse hematologic malignancies, in particular myeloid malignancies and myeloma. FTI therapy is accompanied by a relatively low toxicity profile, thereby providing an important alternative to traditional cytotoxic approaches for elderly patients who are not likely to tolerate or even benefit from aggressive chemotherapy. Current laboratory and clinical studies continue to define the determinants of FTI antitumor activity and resistance. The full development of FTIs for the therapy of hematologic malignancies will require the design and testing of rational combinations of cytotoxic, biologic and immunomodulatory agents in the laboratory and the clinic.