Anticarcinogenic potential of DNA-repair modulators.
Effects of compounds that inhibit repair of DNA lesions in cells have been reported frequently. The consequences include altered incidence of carcinogenicity in vivo, tumorigenic transformation of cultured cells, mutations, and increased lethality as well as sister-chromatid exchanges and chromosome aberrations. This literature is reviewed here, with major emphasis on methylxanthines (caffeine in particular) and nicotinamide analogs. Existing information is also summarized on a novel potent repair inhibitor, beta-lapachone. Compounds that inhibit both DNA replication and repair are not discussed in detail since they have been reviewed often, but miscellaneous inhibitors of repair are summarized in a table. The relatively small number of experiments performed on the anticarcinogenic effects of methyl-xanthines and nicotinamide analogs gave very conflicting results. Some investigators report decreased carcinogenicity of DNA-damaging agents when caffeine was provided, but others obtained the opposite effect. The three studies with nicotinamide analogs all reported enhanced tumorigenicity of carcinogens. The data are too few to enable firm conclusions to be drawn regarding the possibility of using repair inhibitors to prevent cancer in humans. Variations of experimental conditions, carcinogens, cells, etc. have provided conflicting results. The possibility of cancer prevention is, nevertheless, so important that further investigations with DNA-repair inhibitors, particularly with human cells, seem very well justified.
Boothman
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DA
Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, Boston, MA 02115.
Schlegel
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R
Pardee
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AB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004260:DNA Repair; D009285:Naphthoquinones / Q000494:pharmacology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D002273:Carcinogens; D009285:Naphthoquinones; D014970:Xanthines; D009536:Niacinamide; C014638:beta-lapachone