title: Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells.
abstract: BCR-ABL fusion proteins exhibit elevated tyrosine kinase activity and transforming properties. Genetic and biochemical data suggest that Ras activation plays a central role in leukemogenic transformation by BCR-ABL. Imatinib (Novartis, Basel, Switzerland) is a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL. Although imatinib has shown promise against Ph-positive leukemia in human clinical trials, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for combination chemotherapy to eradicate this disease. In the present study, combined use of a farnesyl transferase inhibitor, SCH66336 (lonafarnib), with the antileukemic agents imatinib, daunorubicin, cytosine arabinoside, or etoposide was investigated by cell proliferation assays. The effects of the combination of SCH66336 and imatinib were also investigated by apoptosis assay and colony-forming assay. In proliferation assays with BCR-ABL-expressing cells, combination of SCH66336 with imatinib or cytosine arabinoside showed enhanced antiproliferative activity, whereas combination of SCH66336 with daunorubicin or etoposide demonstrated an antagonistic effect. The combination of imatinib plus SCH66336 more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. SCH66336 combined with imatinib was shown to induce apoptosis in imatinib-resistant BCR-ABL cells by flow cytometric analysis with an APO2.7 monoclonal antibody. These results indicate that SCH66336 is a promising candidate for use in the treatment of patients with imatinib-resistant, Ph-positive leukemia and that the combination of SCH66336 plus imatinib may be useful to circumvent resistance.
authors.affiliation: First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakajima
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tauchi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sumi
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D051231:Farnesyltranstransferase; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000008:administration & dosage*; D010880:Piperidines / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D014162:Transfection; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D003986:Dibenzocycloheptenes
chemical_list: D019883:Alkyl and Aryl Transferases; D001549:Benzamides; D003561:Cytarabine; D003630:Daunorubicin; D004791:Enzyme Inhibitors; D005047:Etoposide; D051231:Farnesyltranstransferase; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D007377:Interleukin-3; D010879:Piperazines; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011725:Pyridines; D011743:Pyrimidines; C115354:lonafarnib; D003986:Dibenzocycloheptenes