INCREASED KILLING OF PROSTATE, BREAST, COLON, AND LUNG-TUMOR CELLS BYTHE COMBINATION OF INACTIVATORS OF O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE AND N,N'-BIS(2-CHLOROETHYL)-N-NITROSOUREA

The ability of a number of compounds that act as inactivators of O-6-a lkylguanine-DNA alkyltransferase (AGT) to sensitize human tumor cell l ines to the effects of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) we re examined. The AGT inactivators tested included O-6-benzylguanine (B G) and its 8-aza-, 8-bromo-, 8-methyl-, 8-oxo, and 8-amino-derivatives and O-6-[p-(hydroxymethyl)benzyl]guanine. All of these compounds exce pt the 8-amino-derivative were active in greatly increasing the killin g of HT29 colon, Du145 prostate, MCF-7 breast and A549 lung tumor cell s by BCNU. Their activities were comparable to those of BG. Two pyrimi dines, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine and 2,4-diamino-6-b enzyloxy-5-nitropyrimidine, were found to be considerably more potent than BG in enhancing BCNU-induced cell killing. The addition of a ster oid group to the 9-position of BG forming either O-6-benzyl-9-[3-oxo-4 -androsten-17 beta-yloxycarbonyl)methyl]guanine O-6-benzyl-9-[3-oxo-5 alpha-androstan-17 beta-yloxycarbonyl)methyl]guanine also produced com pounds effective in enhancing the cytotoxicity of BCNU when added at 1 0 mu M. These results indicate that a range of potent compounds with p otentially different pharmacokinetics is available to test the hypothe sis that inactivation of AGT overcomes the resistance of many tumor ce lls to nitrosoureas.