bms-214662 and Hematologic-Neoplasms

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), lonafarnib (SCH66336, Sarasar), 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 profile and promising efficacy. Ongoing studies will better determine their mechanism of action and the role of combination with other agents, defining their place in the therapeutic arsenal of hematologic disorders.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzodiazepines; Cell Line, Tumor; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Hematologic Neoplasms; Humans; Imidazoles; Piperidines; Pyridines; Quinolones; ras Proteins; Signal Transduction

Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FPT), and are currently being developed and tested across a wide range of human cancers. Hematologic malignancies, particularly those of myeloid origin, are reasonable disease targets in that they likely overexpress relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), or AKT, that depend upon FPT activity to promote proliferation and survival. Phase I clinical trials using FTIs in acute myelogenous leukemia (AML) and other myeloid malignancies have been performed, demonstrating enzyme target inhibition, low toxicity, and promising response rates. These findings have prompted further development in phase II trials, in order to clarify the response rate and to identify the actual downstream signal transduction targets that may be modified by these agents. It is anticipated that such information will ultimately define the optimal roles of FTIs in patients with AML and other myeloid disorders, facilitate the incorporation of FTIs into current therapeutic strategies for myeloid malignancies, and provide insight into effective methods of combining FTIs with other signal transduction inhibitors.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzamides; Benzodiazepines; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Hematologic Neoplasms; Humans; Imatinib Mesylate; Imidazoles; Leukemia, Myeloid, Acute; Models, Biological; Myeloproliferative Disorders; Piperazines; Pyrimidines; Quinolones; ras Proteins; Signal Transduction