In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl-positive cell lines.
Imatinib mesylate (Gleevec, formerly STI571) is an effective therapy for all stages of chronic myelogenous leukemia (CML). While responses in chronic-phase CML are generally durable, resistance develops in many patients with advanced disease. We evaluated novel antileukemic agents for their potential to overcome resistance in various imatinib-resistant cell lines. Using cell proliferation assays, we investigated whether different mechanisms of resistance to imatinib would alter the efficacy of arsenic trioxide (As2O3) or 5-aza-2-deoxycytidine (decitabine) alone and in combination with imatinib. Our results indicate that resistance to imatinib induced by Bcr-Abl overexpression or by engineered expression of clinically relevant Bcr-Abl mutants does not induce cross-resistance to As2O3 or decitabine. Combined treatment with these agents and imatinib is beneficial in cell lines that have residual sensitivity to imatinib monotherapy, with synergistic growth inhibition achieved only at doses of imatinib that overcome resistance. In some imatinib-resistant cell lines, combination treatments that use low doses of imatinib lead to antagonism. Apoptosis studies suggest that this can be explained in part by the reduced proapoptotic activity of imatinib in resistant cell lines. These data underline the importance of resistance testing and provide a rational approach for dose-adjusted administration of imatinib when combined with other agents.
La Rosée
Paul
P
Oregon Health and Science University Cancer Institute, Division of Hematology and Medical Oncology, Portland, OR 97239, USA.
Johnson
Kara
K
Corbin
Amie S
AS
Stoffregen
Eric P
EP
Moseson
Erika M
EM
Willis
Stephanie
S
Mauro
Michael M
MM
Melo
Junia V
JV
Deininger
Michael W
MW
Druker
Brian J
BJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D001483:Base Sequence; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D010087:Oxides / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*
D001152:Arsenicals; D001549:Benzamides; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; D000077209:Decitabine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D001374:Azacitidine; D000077237:Arsenic Trioxide