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Section of Hematology-Oncology, Department of Medicine, Committee on Clinical Pharmacology, Cancer Research Center, University of Chicago, Chicago, Illinois 60637 [Y. C., L. R. W., M. E. D.]; and Department of Medicine and Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina 27710 [S. M. L., A. B. C.]

O⁶-Benzylguanine (BG) inactivates O⁶-alkylguanine-DNA alkyltransferase (AGT), resulting in an increase in the sensitivity of cells to the toxic effects of O⁶-alkylating agents. BG significantly enhances the cytotoxicity and decreases the mutagenicity of nitrogen mustards [i.e., phosphoramide mustard (PM), melphalan, and chlorambucil], a group of alkylating agents not known to produce O⁶-adducts in DNA. The enhancement is observed in cells irrespective of AGT activity. Exposure of Chinese hamster ovary cells to 100 µM BG results in enhancement in the cytotoxicity of PM (300 µM), chlorambucil (40 µM), and melphalan (10 µM) by 9-, 7-, and 18-fold, respectively. In contrast, mutation frequency after treatment with 300 µM PM is decreased from 259 mutants/10⁶ cells to 22 mutants/10⁶ cells when cells are pretreated with BG. The enhancement of toxicity of these bis-alkylating agents appears to involve cross-link formation, because neither cytotoxicity nor mutagenicity of a mono-alkylating PM analogue is significantly altered when combined with BG. Enhanced cytotoxicity and decreased mutagenicity is concomitant with a dramatic increase in the number of cells undergoing apoptosis when BG is combined with PM, melphalan, or chlorambucil at 72–94 h after treatment. Cell cycle analysis demonstrates that BG alone or combined with nitrogen mustards arrests cells in G₁ phase of the cell cycle. At 16 h after treatment, 11 and 57% of cells treated with PM alone or with BG plus PM are in G₁ phase, respectively. Our data suggest that treatment with BG causes G₁ arrest and drives noncycling cells treated with nitrogen mustards into apoptosis, thus protecting against mutagenic DNA damage introduced by nitrogen mustards.

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