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

Anthony Pegg, Kristin Swenn, Chae Mi-Young, M. Eileen Dolan, Robert C. Moschel

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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, Du 145 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-17β-yloxycarbonyl)methyl]guanine or O6-benzyl-9-[3-oxo-5α-androstan-17β-yloxycarbonyl)methyl]guanine also produced compounds effective in enhancing the cytotoxicity of BCNU when added at 10 μM. 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.

Original languageEnglish (US)
Pages (from-to)1141-1148
Number of pages8
JournalBiochemical Pharmacology
Volume50
Issue number8
DOIs
StatePublished - Oct 12 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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