Feasibility of testing DNA repair inhibitors for mutagenicity by a simple method

Abstract

A simple screening methodology for the determination of mutagenicity of DNA repair inhibitors has been tested in this laboratory. Radiation-resistant E. coli B/r and WP2 hcr+ and hcr- are suitable strains for mutagenicity testing. In these strains irradiated with 40-60 ergs/mm2, chemicals which interfere with repair of ultraviolet-induced pre-mutational lesions can be shown to enhance significantly the frequency of mutations to streptomycin resistance. This phenomenon is termed "mutational synergism" [18,20]. We have attempted to apply the procedure for securing data for "mutational synergism" between ultraviolet (UV) radiation and a number of antimalarial drugs including quinine hydrochloride (50 microgram/ml), quinine hydrobromide (50 microgram/ml), primaquine diphosphate (50 microgram/ml), chloroquine (50 microgram/ml), quinine (50 microgram/ml) and quinacrine dihydrochloride (25 microgram/ml). All drugs tested give synergistic effects with UV light. The synergistic activity ranges from 3- to 35-fold. Quinine and quinacrine dihydrochloride have been found to be much more efficient enhancers of the mutagenic effect of UV than caffeine. In general, we have found that the expression of synergistic action occurs at a concentration well below the minimum inhibitory concentration (MIC) with the drugs tested. The implication of these observations in the establishment of a screening method for the evaluation of the mutagenicity of DNA repair inhibitors is discussed.