title: Inhibition of acute lymphoblastic and myeloid leukemias by a novel kinase inhibitor.
abstract: In recent years, synthetic tyrosine kinase inhibitors have made a rapid transition from basic research to therapeutic application. These compounds represent a major clinical advance in the approach to cancer in their relative specificity of action and decreased toxicity. We report here the effects of a novel tyrosine kinase inhibitor CR4 that interferes with growth-promoting pathways to markedly inhibit the growth and survival of both Philadelphia-positive and -negative acute lymphoblastic leukemia (ALL) as well as acute myeloid leukemia (AML). While efficiently ablating leukemic cell growth, normal cell growth and differentiation remain unaffected by CR4. CR4 demonstrates an ability to inhibit the function of multiple growth-critical kinases and yet exhibits a low level of cytotoxicity. These findings suggest that CR4 may prove to be highly effective as a therapeutic agent.
authors.affiliation: Division of Immunology and Allergy, Department of Paediatrics, Infection, Immunity, Injury and Repair Program, The Research Institute of Hospital for Sick Children, 555 University Ave, Toronto, ON, Canada, M5G 1X8.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grunberger
authors.forename: Peter
authors.initials: P
authors.lastname: Demin
authors.forename: Olga
authors.initials: O
authors.lastname: Rounova
authors.forename: Nigel
authors.initials: N
authors.lastname: Sharfe
authors.forename: Lorand
authors.initials: L
authors.lastname: Cimpean
authors.forename: Harjit
authors.initials: H
authors.lastname: Dadi
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Chaim M
authors.initials: CM
authors.lastname: Roifman
mesh_terms: D000208:Acute Disease; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D017254:Leukemic Infiltration / Q000188:drug therapy / Q000517:prevention & control; D051379:Mice; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases