Farnesyltransferase inhibitors in acute myeloid leukemia and myelodysplastic syndromes.
Farnesyltransferase inhibitors were initially developed as Ras inhibitors as they inhibit the prenylation necessary for Ras activation. It is clear now that their mechanism of action is more complex and probably involves other proteins unrelated to Ras. At least 3 drugs within this family have been investigated in acute myeloid leukemia, myelodysplastic syndromes, and other leukemias. These are tipifarnib (R115777, Zarnestra), lonafarnib (SCH66336, Sarasar), and BMS-214662. The first 2 are administered orally, whereas BMS-214662 is given intravenously. These drugs are at different stages of development, and design of treatment schedules and methodology of the available studies are very different. Although most of the information is still preliminary, these agents have demonstrated clear evidence of clinical activity in these diseases and very favorable toxicity profiles. Several studies are still ongoing to better define the efficacy of these agents in the treatment of leukemias, as well as to determine the best schedules, the role of combination with other agents, and the role of these agents in different settings, such as the management of minimal residual disease. It is very possible that these agents will soon find their way to the ranks of established agents for the management of myeloid malignancies
Cortes
Jorge
J
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston 77030, USA. jcortes@mdanderson.org
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001569:Benzodiazepines / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D051231:Farnesyltranstransferase; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D010880:Piperidines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D001569:Benzodiazepines; D051231:Farnesyltranstransferase; D007093:Imidazoles; D010880:Piperidines; D011725:Pyridines; D015363:Quinolones; C115354:lonafarnib; D003986:Dibenzocycloheptenes; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine; C402769:tipifarnib