Farnesyl transferase inhibitors in myeloid malignancies.
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.
Lancet
Jeffrey E
JE
University of Rochester, James P. Wilmot Cancer Center, 601 Elmwood Avenue, Box 704 Rochester, NY 14642, USA. jeffrey_lancet@urmc.rochester.edu
Karp
Judith E
JE
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D001569:Benzodiazepines / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000188:drug therapy; D010879:Piperazines; D011743:Pyrimidines / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D015363:Quinolones; D001569:Benzodiazepines; D000068877:Imatinib Mesylate; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine; C402769:tipifarnib