DNA strand breaks induced by the anti-topoisomerase II bis-dioxopiperazine ICRF-193.
The bis-dioxopiperazine ICRF-193 has long time been considered as a pure topoisomerase II catalytic inhibitor able to exert its inhibitory effect on the enzyme without stabilization of the so-called cleavable complex formed by DNA covalently bound to topoisomerase II. In recent years, however, this concept has been challenged, as a number of reports have shown that ICRF-193 really "poisons" the enzyme, most likely through a different mechanism from that shown by the classical topoisomerase II poisons used in cancer chemotherapy. In the present investigation, we have carried out a study of the capacity of ICRF-193 to induce DNA strand breaks, as classical poisons do, in cultured V79 and irs-2 Chinese hamster lung fibroblasts using the comet assay and pulsed-field gel electrophoresis (PFGE). Our results clearly show that ICRF-193 readily induces breakage in DNA through a mechanism as yet poorly understood.
Hajji
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Department of Cell Biology, Faculty of Biology, University of Seville, Avda. Reina Mercedes no. 6, 41012 Seville, Spain.
Pastor
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Mateos
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S
Domínguez
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I
Cortés
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F
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D006224:Cricetinae; D003412:Cricetulus; D004249:DNA Damage / Q000187:drug effects*; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D016521:Electrophoresis, Gel, Pulsed-Field; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D010879:Piperazines / Q000633:toxicity*; D059005:Topoisomerase II Inhibitors
D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D009153:Mutagens; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione