Cortvrindt R, Bernheim J, Buyssens N, Roobol K
Department of Pathology, University of Antwerp, Willrijk, Belgium.
Br J Cancer. 1987 Sep;56(3):261-5. doi: 10.1038/bjc.1987.187.
The antiproliferative effects of 5-azacytidine (acaCyd) and 5-aza-2'-deoxycytidine (azadCyd) were studied in murine B16 melanoma and a series of B16 melanoma derived mutant strains with selective resistances to the respective drugs. The in vitro cytotoxicities of azaCyd and azadCyd on B16 wild type, expressed in terms of IC50 values, were found to be 5 microM and 0.2 microM, respectively. The in vitro cytotoxicity of both drugs was dependent on the duration of exposure. Uridine and cytidine were able to reverse the in vitro cytotoxicity of azaCyd, but not of azadCyd. Conversely, 2'-deoxycytidine was able to reverse the cytotoxic effect of azadCyd but not of azaCyd. Thymidine and 2'-deoxyuridine had no detectable effects on the in vitro cytotoxicity of either azaCyd or azadCyd. B16 melanoma mutant strains that were selected for resistance to azaCyd showed no cross-resistance to azadCyd, cytosine arabinoside or the fluorinated pyrimidine analogues FUrd, FCyd, FdUrd and FdCyd. Mutant strains that were selected for resistance to azadCyd showed no cross-resistance to azaCyd or fluorinated pyrimidine analogs, but only to cytosine arabinoside. The combined data suggest that azaCyd and azadCyd follow different routes of intracellular metabolic activation and exert their cytotoxic activity via different intracellular targets.
研究了5-氮杂胞苷（acaCyd）和5-氮杂-2'-脱氧胞苷（azadCyd）对小鼠B16黑色素瘤及一系列对相应药物具有选择性抗性的B16黑色素瘤衍生突变株的抗增殖作用。发现azaCyd和azadCyd对B16野生型的体外细胞毒性（以IC50值表示）分别为5 microM和0.2 microM。两种药物的体外细胞毒性均取决于暴露时间。尿苷和胞苷能够逆转azaCyd的体外细胞毒性，但不能逆转azadCyd的。相反，2'-脱氧胞苷能够逆转azadCyd的细胞毒性作用，但不能逆转azaCyd的。胸苷和2'-脱氧尿苷对azaCyd或azadCyd的体外细胞毒性均无明显影响。对azaCyd具有抗性的B16黑色素瘤突变株对azadCyd、阿糖胞苷或氟化嘧啶类似物FUrd、FCyd、FdUrd和FdCyd无交叉抗性。对azadCyd具有抗性的突变株对azaCyd或氟化嘧啶类似物无交叉抗性，但仅对阿糖胞苷有交叉抗性。综合数据表明，azaCyd和azadCyd遵循不同的细胞内代谢激活途径，并通过不同的细胞内靶点发挥其细胞毒性活性。
