Circumvention of resistance by doxorubicin, but not by idarubicin, in a human leukemia cell line containing an intercalator-resistant form of topoisomerase II: evidence for a non-topoisomerase II-mediated mechanism of doxorubicin cytotoxicity.
The novel, topoisomerase II-reactive anthracycline intercalator idarubicin (IDA) was demonstrated to produce protein-associated DNA cleavage in HL-60 human leukemia cells. Like a host of other antineoplastic intercalating agents, IDA produced this effect to a much lesser extent in HL-60/AMSA cells, a line that is primarily resistant to the intercalator amsacrine, but is cross-resistant to a variety of topoisomerase II-reactive DNA intercalating agents including IDA. This resistance is thought to be secondary to the resistance of the topoisomerase II within HL-60/AMSA cells. Surprisingly, HL-60/AMSA cells were minimally resistant to the cytotoxic and DNA cleaving actions of another anthracycline, doxorubicin (ADR). Comparing other effects of the two anthracyclines revealed that IDA, but not ADR, produced endonucleolytic cleavage, a marker of apoptosis. These results suggest that DNA intercalating anthracyclines can have different effects in human leukemia cells. In the case of IDA, drug actions were similar to those produced by the majority of intercalating agents examined in this cellular system. In the case of ADR, the ability to circumvent the resistance of HL-60/AMSA suggests additional, non-topoisomerase II-mediated mechanisms of cytolysis that may also explain the broad spectrum of clinical activity of ADR.
University of Texas, M.D. Anderson Cancer Center, Houston 77030.
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Zwelling
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Bales
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Altschuler
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Mayes
D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004277:DNA, Single-Stranded; D007364:Intercalating Agents; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; D015255:Idarubicin