In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents.
The BCR/ABL tyrosine kinase has been implicated in the pathogenesis of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). STI571 is a novel anticancer agent that selectively inhibits the BCR/ABL tyrosine kinase. The cytotoxic effects of STI571 were studied in combination with antileukemic agents against Ph(+) leukemia cell lines, KU812, K-562, TCC-S, and TCC-Y. The cells were exposed to STI571 and to other agents simultaneously for 5 or 7 days. Cell growth inhibition was determined by MTT assay. The cytotoxic effects in combinations at the inhibitory concentration of 80% level were evaluated by the isobologram. STI571 produced synergistic effects with recombinant and natural alpha-interferons in 2 of 3 and 3 of 3 cell lines, respectively. STI571 produced additive effects with hydroxyurea, cytarabine, homoharringtonine, doxorubicin, and etoposide in all 4 cell lines. STI571 with 4-hydroperoxy-cyclophosphamide, methotrexate, or vincristine produced additive, antagonistic, and synergistic effects in 3 of 4 cell lines, respectively. These findings suggest that the simultaneous administration of STI571 with other agents except methotrexate would be advantageous for cytotoxic effects against Ph(+) leukemias. Among them, the simultaneous administration of STI571 and alpha-interferons or vincristine would be highly effective against Ph(+) leukemias and these combinations would be worthy of clinical trials. In contrast, the simultaneous administration of STI571 with methotrexate would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving STI571. (Blood. 2001;97:1999-2007)
Kano
Y
Y
Division of Hematology and Medical Oncology, Tochigi Cancer Center, Tochigi, Japan. ykano@tcc.pref.tochigi.jp
Akutsu
M
M
Tsunoda
S
S
Mano
H
H
Sato
Y
Y
Honma
Y
Y
Furukawa
Y
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006248:Harringtonines / Q000494:pharmacology; D000077863:Homoharringtonine; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000494:pharmacology; D007938:Leukemia / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008727:Methotrexate / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D006248:Harringtonines; D016898:Interferon-alpha; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D014750:Vincristine; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D006918:Hydroxyurea; D008727:Methotrexate