Rockwell S, Keyes S R, Sartorelli A C
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510-8040.
Cancer Res. 1988 Oct 1;48(19):5471-4.
Aerobic and hypoxic cultures of EMT6 mouse mammary tumor cells were used to study the effects of dicoumarol (DIC) on the cytotoxicity of mitomycin C (MC). DIC protected aerobic cells from MC toxicity, but sensitized hypoxic cells to the cytotoxic actions of this antibiotic. Survival curves for cells treated with 1.5 microM MC +/- 100 microM DIC for different periods of time under aerobic or hypoxic conditions showed that DIC acted as a dose-modifying agent, that is, an agent which changed the slopes, but not the shapes, of the MC survival curves. Experiments that examined the effects of the DIC concentration on the modulation of MC cytotoxicity revealed significant perturbations in MC toxicity with a DIC concentration of 100 microM and increased sensitization/protection with increasing levels of DIC. DIC altered the toxicity of MC only when it was present during exposure of the cells to MC. Treatment with DIC before or after (but not during) MC did not alter the amount of cytotoxicity. Addition of DIC to cell cultures seconds before the addition of MC was as effective as addition of DIC 30 min to 2 h before MC. Taken together, these findings suggest that DIC reversibly inhibits one or more enzymes involved in the activation and inactivation of MC, and that this modulation of the enzymatic processing of MC alters the cytotoxicity of the drug.
采用EMT6小鼠乳腺肿瘤细胞的需氧和缺氧培养来研究双香豆素（DIC）对丝裂霉素C（MC）细胞毒性的影响。DIC可保护需氧细胞免受MC毒性，但使缺氧细胞对这种抗生素的细胞毒作用敏感。在需氧或缺氧条件下，用1.5微摩尔/升MC ± 100微摩尔/升DIC处理细胞不同时间的存活曲线表明，DIC起到剂量调节剂的作用，即一种改变MC存活曲线斜率而非形状的试剂。研究DIC浓度对MC细胞毒性调节作用的实验显示，当DIC浓度为100微摩尔/升时，MC毒性出现显著扰动，且随着DIC水平升高，致敏/保护作用增强。DIC仅在细胞暴露于MC期间存在时才会改变MC的毒性。在MC之前或之后（而非期间）用DIC处理不会改变细胞毒性的程度。在添加MC前几秒向细胞培养物中添加DIC与在添加MC前30分钟至2小时添加DIC效果相同。综上所述，这些发现表明DIC可逆性抑制参与MC激活和失活的一种或多种酶，并且这种对MC酶促加工的调节改变了药物的细胞毒性。
