title: The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate.
abstract: Imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective for the early stages of chronic myelogenous leukemia (CML), but remissions induced in advanced-phase CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived. Therefore, the search for agents that enhance the anti-Ph+ effect of imatinib mesylate is warranted. We investigated the combined effects of imatinib mesylate and the third-generation bisphosphonate zoledronate (ZOL) on Ph+ leukemias, because ZOL inhibited the prenylation of Ras-related proteins downstream of Bcr/Abl. First, we identified the potency of ZOL in vitro against human leukemic cell lines, including 2 Ph+ and a P-glycoprotein-overexpressing leukemic cell line. ZOL was also effective in vivo because as it prolonged the survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice who were given xenografts with Ph+ BV173 leukemic cells. Next, we showed the in vitro synergistic effects with ZOL and imatinib mesylate for Ph+ cell lines. ZOL combined with imatinib mesylate showed synergistic effects in vivo that prolonged the survival of mice inoculated with BV173. ZOL only minimally inhibited the growth of normal hematopoietic progenitors in vitro, and mice receiving ZOL or imatinib mesylate or both tolerated these treatments well. These findings indicate that ZOL is a potent antileukemic agent that augments synergistically the anti-Ph+ leukemia activity of imatinib mesylate.
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Segawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Urasaki
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
authors.forename: Fumio
authors.initials: F
authors.lastname: Enjo
authors.forename: Harukuni
authors.initials: H
authors.lastname: Tokuda
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology* / Q000633:toxicity; D004357:Drug Synergism; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D000077268:Pamidronate; D010879:Piperazines / Q000494:pharmacology*; D017368:Protein Prenylation; D011743:Pyrimidines / Q000494:pharmacology*; D000077211:Zoledronic Acid
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D004164:Diphosphonates; D007093:Imidazoles; D010879:Piperazines; D011743:Pyrimidines; D000077211:Zoledronic Acid; D000068877:Imatinib Mesylate; D020559:Monomeric GTP-Binding Proteins; D000077268:Pamidronate