Influence of O6-methylguanine on DNA damage and cytotoxicity of temozoiomide in L1210 mouse leukemia sensitive and resistant to chloroethylnitrosoureas

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Abstract
Temozoiomide is a new anticancer agent which in the early clinical investigation has shown promising anti-tumor activity. It decomposes spontaneously to the active metabolite of DTIC (MTIC). Temozoiomide is more cytotoxic against L1210 than against a subline L1210/BCNU, resistant to chloroethylnitrosoureas. Using [methyl-3H] temozoiomide 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 methyltrlazenes 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 temozoiomide-induced cytotoxicity. In the sensitive cell line L1210, temozoiomide activity was not potentiated by O6mGua pretreatment. Moreover, in L1210/BCNU, O6mGua increased DNA single-strand breaks caused by temozoiomide, suggesting that O6-guanine alkylation induces an excision repair mechanism in cells depleted in AT.

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