Wan C W, Mak T W
Cancer Res. 1979 Oct;39(10):3981-5.
Tetrahydrouridine (THU) is a reduced pyrimidine nucleoside and has been found to be a potent cytidine deaminase inhibitor. We have examined the effect of THU on the action of 1-beta-D-arabinofuranosylcytosine (ara-C) on DNA synthesis and its cytotoxic effect on normal rat kidney (NRK) cells. The results indicated that THU, when present alone, has no effect on the DNA synthesis or viability of the NRK cells. The addition of THU can, however, further increase the cytotoxic effect of sublethal doses of ara-C and can enhance its ability to inhibit DNA synthesis. Studies on the duration of exposure of the NRK cells to ara-C and on the effect of ara-C on synchronized cultures of NRK cells also support the earlier reports that ara C, through its active compound 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, is capable of blocking cells from progression from G1 into S phase of the cell cycle. Furthermore, we have shown that this inhibition is reversible after the drug has been removed. The addition of THU in the presence of noninhibiting levels of ara-C can also result in the blocking of cells from progression into S phase of the cell cycle. Similar to the effect of ara-C, this inhibition is also reversible. These studies suggest that the addition of THU enhances the cytotoxicity of sublethal doses of ara-C and its ability to inhibit DNA synthesis.
四氢尿苷（THU）是一种还原型嘧啶核苷，已被发现是一种有效的胞苷脱氨酶抑制剂。我们研究了THU对1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，ara-C）作用于DNA合成的影响及其对正常大鼠肾（NRK）细胞的细胞毒性作用。结果表明，单独存在时，THU对NRK细胞的DNA合成或活力没有影响。然而，添加THU可进一步增强亚致死剂量阿糖胞苷的细胞毒性作用，并可增强其抑制DNA合成的能力。对NRK细胞暴露于阿糖胞苷的持续时间以及阿糖胞苷对NRK细胞同步培养物的影响的研究也支持了早期的报道，即阿糖胞苷通过其活性化合物1-β-D-阿拉伯呋喃糖基胞嘧啶5'-三磷酸能够阻止细胞从细胞周期的G1期进入S期。此外，我们已经表明，在去除药物后这种抑制是可逆的。在非抑制水平的阿糖胞苷存在下添加THU也可导致细胞被阻止进入细胞周期的S期。与阿糖胞苷的作用类似，这种抑制也是可逆的。这些研究表明，添加THU可增强亚致死剂量阿糖胞苷的细胞毒性及其抑制DNA合成的能力。
