No correlation between the proliferative status of Bcr-Abl positive cell lines and the proapoptotic activity of imatinib mesylate (Gleevec/Glivec).
Imatinib mesylate (Gleevec, formerly STI571) has been shown to be a safe and effective treatment for chronic myelogenous leukemia (CML). However, despite high rates of hematologic and cytogenetic remissions, molecular remissions are rare. Recent work has revealed the existence of a population of Bcr-Abl-positive, quiescent hematopoietic CML stem cells that are insensitive to induction of apoptosis by imatinib ex vivo. Thus, quiescence is postulated as a mechanism of molecular resistance to imatinib. To model a cell population with reduced cell cycle activity in vitro, we applied three different established approaches to block the cell cycle at the G1/S boundary using Bcr-Abl-positive cell lines. Subsequently, the cells were exposed to imatinib and apoptosis after 48 h of treatment was determined by analysis of activated caspase-3 and apoptotic DNA strand breaks. In these models, reduced cell cycle activity did not have a significant impact on the ability of imatinib to induce apoptosis. These data suggest that the proapoptotic activity of imatinib in vitro is not dependent on cell cycle transit. We conclude that resistance of primary CML cells that are insensitive to imatinib may be the result of molecular properties causing drug resistance rather than a consequence of quiescence itself.
La Rosée
Paul
P
Oregon Health & Science University Cancer Institute, Division of Hematology and Medical Oncology, Portland, Oregon 97239, USA.
Shen
Lei
L
Stoffregen
Eric P
EP
Deininger
Michael
M
Druker
Brian J
BJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001752:Blast Crisis / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl