Inhibition of O6-alkylguanine-DNA alkyltransferase and DNase I activities in vitro by some alkylating substances and antineoplastic agents.
The specificities of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase from brain and liver cells of the chick embryo and of DNase I were demonstrated in vitro by their response to substrate DNA pretreated with monofunctional alkylating agents of different O6-guanine alkylating ability and some antineoplastic agents. Treatment of DNA with ethidium bromide, Hoechst 33258, doxorubicin, Fe2+/bleomycin, and suramin resulted in a dose-dependent diminution of alkyltransferase activity (DE50 approximately 5 micrograms/ml, 15 micrograms/ml, 5 micrograms/ml, 5 micrograms/ml, 100 micrograms/ml, respectively). Apart from bleomycin, comparable results were obtained with DNase I. Thermal denaturation of the substrate DNA reduced both alkyltransferase and DNase I activity. No effect was seen with X-irradiation. Cisplatin decreased only DNase I activity. Some topoisomerase II and/or gyrase inhibitors remained without significant effects on the alkyltransferase reaction whereas DNA catabolism by DNase I was diminished in a dose-dependent manner (DE50 between 6.5 and 19 micrograms/ml).
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Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, Federal Republic of Germany.
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D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006690:Bisbenzimidazole / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D002642:Chick Embryo; D004260:DNA Repair / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000494:pharmacology; D003851:Deoxyribonucleases / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004996:Ethidium / Q000494:pharmacology; D005020:Ethyl Methanesulfonate / Q000494:pharmacology; D005038:Ethylnitrosourea / Q000494:pharmacology; D006358:Hot Temperature / Q000009:adverse effects; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008770:Methylnitrosourea / Q000494:pharmacology; D008780:Methyltransferases / Q000187:drug effects*; D009675:Novobiocin / Q000494:pharmacology; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013379:Substrate Specificity / Q000187:drug effects; D013498:Suramin / Q000494:pharmacology; D014965:X-Rays
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D001761:Bleomycin; D009675:Novobiocin; D013498:Suramin; D008770:Methylnitrosourea; D004317:Doxorubicin; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003851:Deoxyribonucleases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D004996:Ethidium; D006690:Bisbenzimidazole; D005038:Ethylnitrosourea