title: Omacetaxine: a protein translation inhibitor for treatment of chronic myelogenous leukemia.
abstract: Chronic myelogenous leukemia (CML) is driven by the Bcr-Abl fusion protein, which is a result of a (9;22) chromosomal translocation. Imatinib, dasatinib, and nilotinib (tyrosine kinase inhibitors, TKI) have revolutionized how CML is treated. Although the majority of patients respond to these kinase inhibitors, a subset becomes resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently approved by the U.S. Food and Drug Administration for Philadelphia-positive CML either in the chronic or the accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m(2) twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in the chronic phase and major hematologic response in 27% of patients in the accelerated phase. Laboratory investigations unraveled the mechanism of action and effectiveness of this agent. Bcr-Abl protein is intrinsically programmed to turn over with a short half-life that makes it susceptible to protein translation inhibitors. Omacetaxine (homoharringtonine) inhibits total protein biosynthesis by binding to A-site cleft of ribosomes. As a corollary to this action, there is a diminution of short-lived proteins, such as Bcr-Abl, followed by cell death. Approval of this first-in-class protein translation inhibitor opens up new avenues for its use in other diseases as well as mechanism-based combinations.
authors: Authors' Affiliations: Departments of Experimental Therapeutics and Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Varsha
authors: V
authors: Gandhi
authors: William
authors: W
authors: Plunkett
authors: Jorge E
authors: JE
authors: Cortes
mesh_terms: D017277:Drug Approval; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006248:Harringtonines / Q000008:administration & dosage*; D000077863:Homoharringtonine; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D006248:Harringtonines; D000077863:Homoharringtonine; D016044:Fusion Proteins, bcr-abl