The combination drug S-1, which contains tegafur, gimeracil, and oteracil potassium, is a fluoropyrimidine-based oral antineoplastic agent in which the principal drug tegafur is a prodrug of fluorouracil （5-FU）. In recent years, many studies have reported eye problems, especially corneal damage, as an adverse effect of S-1 treatment. In this study, we investigated the cytotoxic effects of each of the constituents of S-1 on corneal epithelial cells by measuring viable cell counts and lactate dehydrogenase （LDH） release. Experimental chemosensitivity study for 5-FU and the constituents of S-1 （i.e., tegafur, gimeracil, and oteracil） using a human cell line. We used immortalized human corneal epithelial （HCE-T） cells to estimate viable cell counts （expressed as a percentage of the control cells） and the activity of LDH in a culture medium （expressed as a percentage of the total LDH activity）. Decreases in viable cell counts were noted with 5-FU and tegafur, but a significant elevation in LDH activity was noted only with tegafur. The incidence of damage in cells exposed to tegafur significantly decreased on adding tranylcypromine, an inhibitor of CYP2A6 that metabolizes tegafur to 5-FU. In addition, 5-FU did not elevate LDH activity, which is an indicator of cell membrane disruption, and concentration-dependence was not observed when cells were treated with 5-FU doses of up to 1,000ng/ml. These findings suggest that the disruption of the metabolic activity of the corneal epithelium by 5-FU is involved in the corneal injury mechanism of S-1.
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