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UBC Theses and Dissertations

Synergistic effect of the carcinogen 4-nitroquinoline 1-oxide and the mutagen caffeine on mammalian cells. White, James Franklin

Abstract

Numerous studies on bacterial systems have shown that cell survival following exposure to various mutagens is greatly influenced by the capacity of the cells to repair the induced DNA lesions. Caffeine (1-3-7-trimethyI xanthine), has been shown to reduce this repair-capacity thereby producing mutagenic, and cytotoxic effects. The question was raised as to whether or not caffeine might reduce the repair-capacity of mammalian cells by interacting with the DNA lesions produced by either the carcinogenic, and oncogenic 4-nitroquinoIine l-oxide, or ultraviolet light (UV) irradiation. This was of interest due to the potential applications that synergistic relationships may hold for chemotherapy. An established line of Syrian-hamster cells (BHK-21, clone 13), was used throughout the experiments. Arginine deprivation was employed to arrest the cultured cells at G₁-phase. The mutagenic 4NQO, UV, and caffeine were applied to these non-dividing cells. The caffeine exposure was at varying time intervals prior to, during, and after 4NQO-induced DNA-repair synthesis (unscheduled DNA synthesis). Similarly, caffeine was added to cells immediately following UV-induced DNA-repair synthesis. Exposure of BHK-21 cells to caffeine, and 4NQO appeared to reduce their colony-forming ability to a greater extent than when the cells were exposed to either chemical alone. The addition of caffeine combined with 4NQO to cells, in G₁-phase, did not appear to significantly influence their rate of flow into S-phase, or through to metaphase. The effect of caffeine on 4NQO- (but not UV-) induced DNA-repair synthesis, using isotope labelling, and autoradiography suggested a reduction in the amount of DNA-repair synthesis. This reduction appeared to be dependent on the caffeine concentration, and on the time of exposure of the cells to this chemical. An initial inquiry was made into whether or not this synergistic effect between caffeine and 4NQO-induced DNA-repair synthesis could be detected in human lymphocytes in vitro. However, very low levels of 4NQO-induced DNA-repair synthesis were observed in these cells. It was therefore not conducive for the autoradiographic analysis of DNA-repair synthesis following 4NQO exposure. A model explaining the apparent caffeine suppression of 4NQO-induced DNA-repair synthesis is postulated. The potential medical implications are discussed.

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