thioguanine-anhydrous and 3-aminobenzamide

We have investigated the effect of inhibitors of ADP-ribosyltransferase on the cytotoxicity of a range of S-phase acting drugs. Co-administration of 3 mM 3-aminobenzamide (3AB) potentiated the cytotoxicity of TG 2-fold, but had no effect on the cytotoxicity of HU, FdUrd or araC. Higher concentrations of benzamides (e.g. 10-20 mM 3AB) produced a G1-specific cell cycle blockade. This treatment prevented cells entering S-phase DNA synthesis and consequently protected against the cytotoxicity of the same S-phase acting drugs. Thus, using different treatment regimens with 3AB, it was possible to either potentiate or protect against the cytotoxicity of TG.

Topics: Benzamides; Cell Survival; Cells, Cultured; Cytarabine; DNA Repair; Dose-Response Relationship, Drug; Drug Interactions; Hydroxyurea; Interphase; Poly(ADP-ribose) Polymerase Inhibitors; Thioguanine

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.

Topics: Animals; Benzamides; Cell Cycle; Cell Line; Cell Survival; DNA Repair; Drug Synergism; NAD; Poly(ADP-ribose) Polymerase Inhibitors; Thioguanine