Synergistic enhancement of 6-thioguanine cytotoxicity by ADP-ribosyltransferase inhibitors.
The effect of the adenosine diphosphoribosyltransferase inhibitors, the substituted benzamides, on the cytotoxicity of 6-thioguanine (6TG) was investigated. Nontoxic concentrations of benzamides potentiated the cytotoxicity of 6TG with a dose enhancement factor of 2, producing a 6-fold increase in cell killing at 10% survival. 6TG treatment did not deplete cellular NAD levels, and in the presence of 3-aminobenzamide, there was no increase in the number of 6TG-induced DNA strand breaks. To obtain potentiation of cytotoxicity, 3-aminobenzamide had to be present in late G1-S phase during the cell cycle in which 6TG is incorporated into the DNA. These data indicate that the substituted benzamides potentiate the cytotoxicity of 6TG by a mechanism independent of an inhibition of DNA repair.
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004357:Drug Synergism; D009243:NAD / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013866:Thioguanine / Q000494:pharmacology*
D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009243:NAD; C025160:3-aminobenzamide; D013866:Thioguanine