Effects of nicotinamide, isonicotinamide, and bleomycin on DNA synthesis and repair in rat hepatocytes and hepatoma cells.
Because inhibitors of poly (ADP-ribose) synthetase have been found to influence DNA synthesis in some systems, the possibility that nicotinamide or isonicotinamide might potentiate the effect of bleomycin on DNA replication and repair was examined. After a 30-minute incubation with bleomycin (200 micrograms/ml), tritiated thymidine ([3H]dThd) incorporation into DNA was stimulated during a subsequent 30-minute incubation with hepatocytes of inbred BUF rats but was decreased in HTC cells of BUF rats. When unscheduled DNA synthesis was measured in the presence of 10 mM hydroxyurea, bleomycin (200 micrograms/ml) increased [3H]dThd incorporation in both cell types. A dose of 20 mM nicotinamide and isonicotinamide caused an approximately 50% inhibition of total [3H]dThd incorporation in HTC cells. Significant inhibitory effects of 20 mM nicotinamide and isonicotinamide on unscheduled DNA synthesis were observed after preincubation of hepatocytes and HTC cells with bleomycin. When the effects of bleomycin on DNA structure were assessed fluorometrically with ethidium bromide after mild alkaline incubation, nicotinamide and isonicotinamide did not significantly affect the damage revealed with bleomycin alone. When HTC cells were incubated for 48 hours with bleomycin (20 micrograms/ml), the increase in cell numbers was about 50% of that in control cultures. Nicotinamide and isonicotinamide also inhibited the proliferation of HTC cells, but the effects were not additive with the effect of bleomycin.
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D006918:Hydroxyurea / Q000494:pharmacology; D008099:Liver / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D009536:Niacinamide / Q000494:pharmacology*; D051381:Rats; D011915:Rats, Inbred BUF
D001761:Bleomycin; D009536:Niacinamide; C027681:isonicotinamide; D006918:Hydroxyurea