The relationship of a novel drug-resistant phenotype in C3H10T1/2 cells selected with alkylating agents to neoplastic transformation and ATP metabolism

We investigated the resistance to alkylating agents in parental, drug-selected and neoplastically transformed C3H10T1/2 (10T1/2) murine fibroblasts. Similar levels of resistance to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) were observed in cells selected for resistance to MNNG or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) as well as in cells transformed by a single treatment with MNNG. Surprisingly, neither the levels of O6-alkylguanine-DNA alkyltransferase (AT) nor glutathioneS-transferase (GST) were altered in drug-resistant cells. In contrast, changes in ATP metabolism were observed in both transformed and MNNG-selected cells after treatment with MNNG. Specifically, 3 h after treatment with 5 μg/ml MNNG, ATP levels decreased by 85% and 74% in MNNG-selected and transformed cells, respectively, compared to only a 28% decrease in parental cells. Therefore, rather than contributing to cell sensitivity to alkylating agents, the ability to rapidly utilize ATP and tolerate resulting decreases in ATP levels may in some cases play a role in protection from the cytotoxic effects of alkylating agents.