Increased killing of prostate, breast, colon, and lung tumor cells by the combination of inactivators of O6-alkylguanine-DNA alkyltransferase and N,N'-bis(2-chloroethyl)-N-nitrosourea

Abstract

The ability of a number of compounds that act as inactivators of O6-alkylguanine-DNA alkyltransferase (AGT) to sensitize human tumor cell lines to the effects of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) were examined. The AGT inactivators tested included O6-benzylguanine (BG) and its 8-aza-, 8-bromo-, 8-methyl-, 8-oxo, and 8-amino-derivatives and O6-[p-(hydroxymethyl)benzyl]guanine. All of these compounds except the 8-amino-derivative were active in greatly increasing the killing of HT29 colon, Du145 prostate, MCF-7 breast and A549 lung tumor cells by BCNU. Their activities were comparable to those of BG. Two pyrimidines, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine and 2,4-diamino-6-benzyloxy-5-nitropyrimidine, were found to be considerably more potent than BG in enhancing BCNU-induced cell killing. The addition of a steroid group to the 9-position of BG forming either O6-benzyl-9-[3-oxo-4-androsten-17 beta-yloxycarbonyl)methyl]guanine or O6-benzyl-9-[3-oxo-5 alpha-androstan-17 beta-yloxycarbonyl)methyl]guanine also produced compounds effective in enhancing the cytotoxicity of BCNU when added at 10 microM. These results indicate that a range of potent compounds with potentially different pharmacokinetics is available to test the hypothesis that inactivation of AGT overcomes the resistance of many tumor cells to nitrosoureas.