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.
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.
Yokota
Asumi
A
Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Kimura
Shinya
S
Masuda
Satohiro
S
Ashihara
Eishi
E
Kuroda
Junya
J
Sato
Kiyoshi
K
Kamitsuji
Yuri
Y
Kawata
Eri
E
Deguchi
Yasuyuki
Y
Urasaki
Yoshimasa
Y
Terui
Yasuhito
Y
Ruthardt
Martin
M
Ueda
Takanori
T
Hatake
Kiyohiko
K
Inui
Ken-ichi
K
Maekawa
Taira
T
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*
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