The enhancement of cytotoxicity of N-methyl-N-nitrosourea and of gamma-radiation by inhibitors of poly(ADP-ribose) polymerase

Abstract

Inhibitors of poly(ADP-ribose) polymerase show a synergistic potentiation of cytotoxicity with certain DNA-damaging agents. Non-toxic concentrations of 5-methylnicotinamide dramatically potentiate the cytotoxicity of N-methyl-N-nitrosourea as tested by the cloning ability of mouse leukaemia (L1210) cells. A dose-enhancement factor of about 10 is observed. This potentiation is dependent on the concentration of 5-methylnicotinamide. The methylxanthines theobromine, theophylline and caffeine also increase the cytotoxicity of methylnitrosourea. Thymidine, in the presence of sufficient deoxycytidine to overcome the perturbation of deoxynucleotide metabolism, also potentiates the cytotoxicity of methylnitrosourea. Nicotinate, which is not an inhibitor of poly-(ADP-ribose) polymerase, has no effect on methylnitrosourea toxicity. A very small, but consistent, enhancement of the toxicity of gamma-radiation by the same inhibitors has been observed. We suggest that this potentiation of cytotoxicity is mediated by inhibition of (ADP-ribose)n biosynthesis; and that the biosynthesis is stimulated by DNA damage. We therefore propose that (ADP-ribose)n takes part in cellular repair mechanisms, either by modifying chromatin structure or by a specific participation in DNA repair.