title: Farnesyltransferase inhibitors (FTIs) in myeloid malignancies.
abstract: Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Myeloid malignancies are appropriate disease targets, in that they express relevant biologic targets, such as Ras, Mitogen-Activated Protein Kinase (MAPK), AKT, and others that may depend upon farnesyl protein transferase (FTase) activity to promote proliferation and survival. Phase I trials in acute leukemias and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in a variety of hematologic malignancies and disease settings, in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Room 289, Baltimore, Maryland, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Karp
authors.forename: J E
authors.initials: JE
authors.lastname: Lancet
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D009196:Myeloproliferative Disorders / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase