Factors modifying 3-aminobenzamide cytotoxicity in normal and repair-deficient human fibroblasts

Abstract

3‐Aminobenzamide (3‐AB), an inhibitor of poly(ADP‐ribosylation), is lethal to human fibroblasts with damaged DNA. Its cytotoxicity was determined relative to a number of factors including the types of lesions, the kinetics of repair, and the availability of alternative repair systems. A variety of alkylating agents, UV or gamma irradiation, or antimetabolites were used to create DNA lesions. 3‐AB enhanced lethality with monofunctional alkylating agents only. Within this class of compounds, methylmethanesulfonate (MMS) treatments made cells more sensitive to 3‐AB than did treatment with methylnitrosourea (MNU) or methylnitronitrosoguanidine (MNNG). 3‐AB interfered with a dynamic repair process lasting several days, since human fibroblasts remained sensitive to 3‐AB for 36–48 hours following MMS treatment. During this same interval, 3‐AB caused these cells to arrest in G₂ phase. Alkaline elution analysis also revealed that this slow repair was delayed further by 3‐AB. Human mutant cells defective in DNA repair differed in their responses to 3‐AB. Among mutants sensitive to monofunctional alkylating agents, ataxia telangiectasia cells were slightly more sensitive to 3‐AB than control cells, while Huntington's disease cells had a near‐normal response. Among UV‐sensitive strains, xeroderma pigmentosum variant (XPV) cells were more sensitive to 3‐AB after MMS than were XP complementation group A (A) cells, which responded normally. Greater lethality with 3‐AB could be dependent on inability of the mutant cells to repair damage by other processes.