Production of protein-associated DNA breaks by 8-methoxycaffeine, caffeine and 8-chlorocaffeine in isolated nuclei from L1210 cells: comparison with those produced by topoisomerase II inhibitors.
8-Methoxycaffeine (8-MOC) is a caffeine derivative, more potent than the parent compound, but very similar to caffeine in terms of induction of DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs) and DNA-protein crosslinks (DPCs). We have studied the capability of 8-MOC, caffeine and 8-chlorocaffeine (8-CC) of inducing SSBs, DSBs and DPCs, and we have compared 8-MOC with ellipticine, a typical inhibitor of DNA topoisomerase II. The DNA effects of 8-MOC appeared similar to those of ellipticine. In both cases SSBs, DSBs and DPCs were present in a similar ratio, and they were rapidly reversible after removal of the drug. The dose-response curve was bell-shaped for both compounds. In addition, 8-MOC, caffeine and 8-CC were capable of inhibiting DSBs induced by ellipticine. These results were obtained at the level of L1210 cell nuclei. In spite of these functional similarities, 8-MOC, caffeine and 8-CC were unable to stimulate the formation of a cleavable complex by purified L1210 topoisomerase II (p170 form) when SV40 DNA and human c-myc DNA were used as substrate. These methylated oxypurines could be active on a different form of topoisomerase II, or, alternatively, they could be active only in the natural chromatin 'milieu' within the nucleus.
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Istituto Nazionale per la Ricerca sul Cancro (IST), Genova, Italy.
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Parodi
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Pedrini
A M
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Kohn
K W
KW
Pommier
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Y
D000818:Animals; D001345:Autoradiography; D002110:Caffeine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004279:DNA, Viral / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004611:Ellipticines / Q000494:pharmacology; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D007939:Leukemia L1210 / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D013539:Simian virus 40 / Q000235:genetics; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D004611:Ellipticines; D016271:Proto-Oncogene Proteins c-myc; D059005:Topoisomerase II Inhibitors; C034192:ellipticine; D002110:Caffeine; C066637:8-methoxycaffeine; C071368:8-chlorocaffeine; D004250:DNA Topoisomerases, Type II