title: INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity.
abstract: Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Asumi
authors.initials: A
authors.lastname: Yokota
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sato
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kamitsuji
authors.forename: Eri
authors.initials: E
authors.lastname: Kawata
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Deguchi
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Urasaki
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Terui
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D001921:Brain / Q000473:pathology*; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D007267:Injections; D020014:K562 Cells / Q000187:drug effects / Q000637:transplantation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016572:Cyclosporine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C506918:bafetinib