Influence of O6-methylguanine on DNA damage and cytotoxicity of temozolomide in L1210 mouse leukemia sensitive and resistant to chloroethylnitrosoureas.
Temozolomide is a new anticancer agent which in the early clinical investigation has shown promising antitumor activity. It decomposes spontaneously to the active metabolite of DTIC (MTIC). Temozolomide is more cytotoxic against L1210 than against a subline L1210/BCNU, resistant to chloroethylnitrosoureas. Using [methyl-3H] temozolomide we found that after 1 h exposure the amount of O6-methylguanine (O6mGua) was twice as high in L1210 than in L1210/BCNU whereas the amount of N7 mGua was approximately the same in the two cell lines. O6-alkylguanine DNA alkyltransferase (AT) levels were higher in L1210/BCNU than in L1210, supporting the view that the resistance to methyltriazenes is probably related to the efficient repair of O6mGua in L1210/BCNU. Exposure of L1210/BCNU cells to 0.4 mM O6mGua for 24 h resulted in a depletion of AT and in a higher temozolomide-induced cytotoxicity. In the sensitive cell line L1210, temozolomide activity was not potentiated by O6mGua pretreatment. Moreover, in L1210/BCNU, O6mGua increased DNA single-strand breaks caused by temozolomide, suggesting that O6-guanine alkylation induces an excision repair mechanism in cells depleted in AT.
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Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
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Bonfanti
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D000468:Alkalies; D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004351:Drug Resistance / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy*; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D009607:Nitrosourea Compounds / Q000494:pharmacology; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D000468:Alkalies; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009607:Nitrosourea Compounds; D006147:Guanine; D003606:Dacarbazine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide