Farnesyltransferase inhibition in hematologic malignancies: the clinical experience with tipifarnib.
Increased understanding of the cellular mechanisms associated with various malignancies has allowed researchers to develop agents that selectively target the cellular proteins and pathways implicated in the pathogenesis of malignancy. Tipifarnib is a specific and potent farnesyltransferase inhibitor that demonstrates in vivo and in vitro activity against a variety of human cancers. Although tipifarnib was initially thought to target the Ras protein, recent evidence suggests that the presence of ras mutations is not necessary for the antitumor effects of tipifarnib, and that tipifarnib may exert its effects downstream of Ras. The oral administration and favorable toxicity profile of tipifarnib, combined with its activity in a variety of intracellular pathways that have been implicated in the pathogenesis of hematologic malignancies, make it an especially attractive agent for use in patients with acute myeloid leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), and multiple myeloma. Because hematologic malignancies are likely driven by multiple genetic aberrations, the most effective treatment strategy will likely combine multiple agents with complementary mechanisms of action. Thus, additional studies of combination regimens that incorporate tipifarnib with other antineoplastic agents are crucial. Early results from studies combining tipifarnib with imatinib or etoposide in CML and AML have been promising and warrant further evaluation in larger clinical trials.
Martinelli
Giovanni
G
Institute of Hematology and Medical Oncology, University of Bologna, 40138 Bologna, Italy. giovanni.martinelli2@unibo.it
Iacobucci
Ilaria
I
Paolini
Stefania
S
Ottaviani
Emanuela
E
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D015363:Quinolones / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib