Cytotoxicity and induction of sister chromatid exchanges in human and rodent brain tumor cells treated with alkylating chemotherapeutic agents

Abstract

Rodent (9L and 9L-2) and human (SF-126 and SF-188) brain tumor cells were treated with methylating, ethylating, and chloroethylating nitrosoureas. 9L-2 and SF-188 cells were 10-fold and 5.4-fold more resistant to the cytotoxic effects of 1-(2-chloroethyl)-1-nitrosourea (CNU) than were 9L and SF-126 cells. SF-188 cells were 2.5- to 3-fold more resistant to N-methyl-N-nitrosourea (MNU) and streptozotocin (STZ) than SF-126 cells. 9L-2 cells were slightly more resistant to the cytotoxic effects of STZ and MNU than were 9L cells, but the rodent cells were 5- to 15-fold more resistant to these agents than the human cells. There were only small differences in cytotoxicity among the four cell lines after treatment with N-ethyl-N-nitrosourea (ENU). SF-188 and 9L-2 cells were 7- to 8-fold more resistant to the induction of sister chromatid exchange (SCEs) by CNU than were SF-126 and 9L cells. SF-126 cells were 80-fold more sensitive to the induction of SCEs by both STZ and MNU than were SF-188 cells. Only small differences in SCE induction were observed in 9L and 9L-2 cells treated with MNU and STZ. After ENU treatment, SF-126, 9L, and 9L-2 cells showed similar levels of SCEs; SF-188 cells were more resistant to the induction of SCEs by ENU. Pretreatment of 9L-2 cells with MNU resulted in a dose-dependent increase in cytotoxicity and SCE induction by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Treatment with 1 mM MNU completely reversed the cellular resistance of 9L-2 cells to BCNU but did not potentiate either cytotoxicity or SCE induction in 9L cells. These results suggest that O6-alkylguanine-DNA-alkyltransferase (O6-AT) plays an important role in determining the cytotoxicity of and the induction of SCEs by CNU in both rodent and human tumor cells. O6-AT may also influence the response of human cells to both the cytotoxic effects of and the induction of SCEs by MNU and STZ. In the rodent cells, however, biochemical mechanisms other than O6-AT appear to determine the cytotoxic response to these agents. O6-AT does not appear to influence the cytotoxicity of ENU in either human or rodent cells but may have a small effect on SCE induction in human cells.