Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells.
Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl-positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl-positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl-expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.
Thiesing
J T
JT
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, OR 97201, USA.
Ohno-Jones
S
S
Kolibaba
K S
KS
Druker
B J
BJ
D000970:Antineoplastic Agents / Q000633:toxicity*; D001549:Benzamides; D001752:Blast Crisis; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000633:toxicity; D003630:Daunorubicin / Q000633:toxicity; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D006918:Hydroxyurea / Q000633:toxicity; D000068877:Imatinib Mesylate; D007377:Interleukin-3 / Q000494:pharmacology; D007947:Leukemia, Megakaryoblastic, Acute; D010879:Piperazines / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051562:Proto-Oncogene Proteins c-bcr; D011743:Pyrimidines / Q000633:toxicity*; D019089:Stem Cell Factor / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D001549:Benzamides; D007377:Interleukin-3; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D019089:Stem Cell Factor; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D006918:Hydroxyurea; D003630:Daunorubicin