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Blood, 1 April 2001, Vol. 97, No. 7, pp. 1999-2007
HEMATOPOIESIS
In vitro cytotoxic effects of a tyrosine kinase
inhibitor STI571 in combination with commonly used
antileukemic agents
Yasuhiko Kano,
Miyuki Akutsu,
Saburo Tsunoda,
Hiroyuki Mano,
Yuko Sato,
Yoshio Honma, and
Yusuke Furukawa
From the Division of Hematology and Medical Oncology,
Tochigi Cancer Center, Tochigi, Japan; Divisions of Molecular
Hematopoiesis and Molecular Biology, Jichi Medical School, Tochigi,
Japan; Division of Molecular Cytogenetics, Department of Clinical
Pathology, Research Institute, International Medical Center of Japan,
Tokyo, Japan; and Division of Chemotherapy, Saitama Cancer Center
Research Institute, Saitama, Japan.
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  -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
-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.
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