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 chro nic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) a cute lymphoblastic leukemia (ALL). ST1571 is a novel anticancer agent that selectively inhibits the BCR/ABL tyrosine kinase. The cytotoxic effects of ST1571 were studied in combination with antileukemic agents against Ph+ leu kemia cell lines, KU812, K-562, TCC-S, and TCC-Y. The cells were exposed to ST1571 and to other agents simultaneously for 5 or 7 days. Cell growth inh ibition was determined by MTT assay. The cytotoxic effects in combinations at the inhibitory concentration of 80% level were evaluated by the isobolog ram. ST1571 produced synergistic effects with recombinant and natural alpha -interferons in 2 of 3 and 3 of 3 cell lines, respectively. ST1571 produce d additive effects with hydroxyurea, cytarabine, homoharringtonine, doxorub icin, and etoposide in all 4 cell lines. ST1571 with 4-hydroperoxycyclophos phamide, methotrexate, or vincristine produced additive, antagonistic, and synergistic effects in 3 of 4 cell lines, respectively. These findings sugg est that the simultaneous administration of ST1571 with other agents except methotrexate would be advantageous for cytotoxic effects against Ph+ leuke mias. Among them, the simultaneous administration of ST1571 and alpha -inte rferons or vincristine would be highly effective against Ph+ leukemias and these combinations would be worthy of clinical trials. In contrast, the sim ultaneous administration of ST1571 with methotrexate would have little ther apeutic efficacy. Although there are gaps between in vitro studies and clin ical trials, the present findings provide useful information for the establ ishment of clinical protocols involving ST1571. (Blood, 2001; 97:1999-2007) (C) 2001 by The American Society of Hematology.