In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells.
BACKGROUND
Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR-ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR-ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR-ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML.


METHODS
The single agents and their combinations were studied for in vitro effect on proliferation of BCR-ABL positive cell lines KBM5 and KBM7 by 3(4,5-dimethylthiazol-2yl)-2,5 diphenyl-tetrazolium bromide assay and on primary patient-derived BCR-ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer-assisted analysis using the CalcuSyn software.


RESULTS
STI571 consistently suppressed BCR-ABL positive cell proliferation with a dose-effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML-derived clonogenic cells in semisolid cultures.


CONCLUSIONS
In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome-positive leukemias.
Scappini
Barbara
B
Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Onida
Francesco
F
Kantarjian
Hagop M
HM
Dong
Li
L
Verstovsek
Srdan
S
Keating
Michael J
MJ
Beran
Miloslav
M
D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006248:Harringtonines / Q000008:administration & dosage / Q000494:pharmacology; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D006248:Harringtonines; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases