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Correlation of Enhanced 6-Mercaptopurine Cytotoxicity with Increased Phosphoribosylpyrophosphate Levels in Chinese Hamster Ovary Cells Treated with 3-Aminobenzamide¹

Cancer Research Unit, University of Newcastle upon Tyne, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, United Kingdom

3-Aminobenzamide (3AB) has been used widely to inhibit the nuclear enzyme poly(ADP-ribose) polymerase (EC 2.4.2.30) and study the involvement of poly(ADP-ribose) synthesis in DNA repair and other cellular functions. 3AB (3 mM) potentiates the cytotoxicity of 6-mercaptopurine (MP) and azathioprine in CHO-K1 cells with dose enhancement factors at 10% survival of 30-fold. In synchronized cells, 3AB is required during G₁ and early S phase to obtain potentiation of MP cytotoxicity. There is a small but significant depletion of cellular NAD in MP-treated cells. As demonstrated by flow cytometric analysis, 20–40 µM MP causes an accumulation of cells in early S phase of the cell cycle. 3AB (3 mM) has no effect on cell cycle distribution; however, in the presence of MP, a similar accumulation is seen by 2–5 µM MP. 3AB and MP per se have no effect on phosphoribosylpyrophosphate levels, but coincubation causes a 30-fold increase in phosphoribosylpyrophosphate levels, reaching a maximum by 1.5 µM MP and declining to basal levels by 10 µM MP. There was a good correlation between the 3AB dose-dependent increase in cell killing and rise in phosphoribosylpyrophosphate levels.

¹ Supported by grants from the North of England Cancer Research Campaign and the Leukaemia Research Fund.

² To whom requests for reprints should be addressed.

Received 5/10/89. Revised 10/30/89.

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