POTENTIATION OF TEMOZOLOMIDE-INDUCED CYTOTOXICITY - A COMPARATIVE-STUDY OF THE BIOLOGICAL EFFECTS OF POLY(ADP-RIBOSE) POLYMERASE INHIBITORS

Four poly(ADP-ribose) polymerase (PADPRP) inhibitors U-aminobenzamide, benzamide, 3,4-dihydro-5-methoxyisoquinolin-1 (2H)-one (PD 128763) an d 8-hydroxy-2-methylquinazolin-4(3H)-one (NU1025)] were compared with respect to their effects on a number of biological end points. The fol lowing parameters were assessed: their ability to inhibit the enzyme i n permeabilised L1210 cells; their ability to potentiate the cytotoxic ity of temozolomide (including the cytotoxicity of the compounds per s e); their ability to increase net levels of temozolomide-induced DNA s trand breaks and inhibit temozolomide-induced NAD depletion. PD 128763 and NU1025 were equipotent as PADPRP inhibitors, and 40- and 50-fold more potent than benzamide and 3-aminobenzamide respectively. All the compounds acted in a concentration-dependent manner to potentiate the cytotoxicity and increase DNA strand break levels in cells treated wit h temozolomide. There was an excellent correlation between the potency of the compounds as PADPRP inhibitors and their effects on cell survi val and DNA repair. Temozolomide treatment caused a decrease in cellul ar NAD levels, and this was abolished by the PADPRP inhibitors. In con clusion, the new generation of PADPRP inhibitors are at least 50-fold more effective than 3-aminobenzamide as chemopotentiators, and can be used at micromolar rather than millimolar concentrations in intact cel ls.