Sulfhydryl-related reduction of the mitotic inhibition and cell inactivation induced by pyrimidine analogs

Sulfhydryl-related reduction of the mitotic inhibition and cell inactivation induced by the pyrimidine analogs NY 3170, NY 4137 and NY 4138 was investigated. Human NHIK 3025 cells grown in culture were treated with the SH-compounds glutathione (GSH) and cysteine, and the S-S-compound cystine in combination with the above pyrimidine analogs. Simultaneous combination of GSH or cysteine with NY 4137 (a pyrimidine sulfone) abolished the ability of the drug to arrest cells in metaphase, while simultaneous combination of NY 4137 with cystine had no such effect. The mitigating effect of GSH and cysteine was dose-dependent and maximal at 1 mM GSH or 2.5 mM cysteine. In combination with NY 4138 (a pyrimidine sulfoxide) GSH and cysteine, but not cystine, reduced slightly the ability of NY 4138 to accumulate cells in mitosis. By contrast, neither GSH, cysteine nor cystine affected the mitotic inhibiting property of NY 3170 when in simultaneous combination with this pyrimidinone. With respect to cell inactivation, an increase in the fraction of cells surviving treatment with NY 4137 was found when GSH or cysteine, but not cystine, was simultaneously present. In order to evaluate the importance of endogenous SH-groups, we measured the effect of NY 4137 on NHIK 1922-C3 cells, a mouse-human hybrid, having a lower endogenous sulfhydryl content than NHIK 3025 cells. Treatment of these cells with NY 4137 resulted in a lower surviving fraction of cells than identical treatment of NHIK 3025 cells.