Override of the radiation-induced mitotic block in human tumour cells by methylxanthines and its relationship to the potentiation of cytotoxicity.
The four methylated xanthine derivatives, caffeine, theophylline, theobromine and paraxanthine, were tested for their ability to override the mitotic block induced by ionizing radiation in the human bladder carcinoma cell line RT112. All four agents were found to partially override the block, ranking in terms of potency at a concentration of 1 mM in the order caffeine greater than theophylline greater than theobromine = paraxanthine. However, the effects of the four agents on the clonal survival of irradiated cells failed to correlate with the extent of override, both in terms of the relative effects of the four agents and the dose-response relationships; at a concentration of 1 mM only caffeine was found to potentiate cell killing as well as causing block override, whilst at higher concentrations all the agents had a significant effect on survival but little or no further influence on the degree of block override. It is therefore concluded that override of a mitotic block is not in itself sufficient to cause the increased killing seen when irradiated cells are incubated in the presence of caffeine, and that caffeine exerts its potentiating effect either by directly inhibiting repair of damage in DNA or by causing override of the radiation-induced inhibition of DNA synthesis.
Musk
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SR
Radiotherapy Research Unit, Institute of Cancer Research, Sutton, Surrey, UK.
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GG
D002110:Caffeine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D066298:In Vitro Techniques; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects*; D013805:Theobromine / Q000494:pharmacology; D013806:Theophylline / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects*; D001749:Urinary Bladder Neoplasms / Q000473:pathology; D014970:Xanthines / Q000494:pharmacology*
D014970:Xanthines; D002110:Caffeine; D013806:Theophylline; D013805:Theobromine; C021183:1,7-dimethylxanthine