CARCINOGENICITY AND HEMOGLOBIN-SYNTHESIS INDUCTION BY CYTIDINE ANALOGS
CARCINOGENICITY AND HEMOGLOBIN-SYNTHESIS INDUCTION BY CYTIDINE ANALOGS
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DOI：
10.1038/bjc.1988.89
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发表时间：
1988-04-01
影响因子：
8.8
通讯作者：
WINBERG, CD
中科院分区：
文献类型：
--
作者：
CARR, BI;RAHBAR, S;WINBERG, CD
我们研究了5-氮杂胞苷及其五种类似物：（1）在雄性Fischer大鼠中的致癌性;（2）使用体内大鼠体重变化和体外细胞毒性试验的毒性;以及（3）血红蛋白基因表达，使用绵羊、小鼠和大鼠中的少量血红蛋白合成。5-发现氮杂胞苷是一种完全致癌物。在接受12个月治疗的大鼠中，它增加了睾丸肿瘤和非睾丸肿瘤的发病率。5-氮杂胞苷还具有肝肿瘤促进特性，并且在定时妊娠的第21天给予妊娠大鼠时能够诱导经胎盘致癌作用。在小型实验中，其他5种类似物都没有致癌性。所有已知具有低甲基化活性的类似物在体外均具有细胞毒性;最有效的是5-氮杂胞苷。通过与未处理对照组相比大鼠体重降低来判断，氟化胞苷类似物和5“-脱氧氮杂胞苷比5-氮杂胞苷毒性更大。在大鼠和DBA/2 J小鼠中观察到血红蛋白合成的改变，但在绵羊中未观察到。在小鼠中，观察到最明显的血红蛋白变化，使用高剂量和低剂量的5-氮杂胞苷以及5，6-二氢-5-氮杂胞苷和5-氮杂-2”-脱氧胞苷时，发现少量血红蛋白合成增加。在这些实验中，这最后两种类似物似乎相对无毒、无致癌性，并保留血红蛋白活化特性，其效力与5-氮杂胞苷相似。
We investigated 5-azacytidine and five of its analogues for: (1) carcinogenicity, in the male Fischer rat; (2) toxicities using changes in rat weights in vivo and a cytotoxicity assay in vitro; and (3) haemoglobin gene expression, using minor haemoglobin synthesis in sheep, mice and rats. 5-Azacytidine was found to be a complete carcinogen. It increased the incidence of testicular tumours as well as non-testicular tumours in rats treated for 12 months. 5-Azacytidine also had hepatic tumour promoting properties and was able to induce transplacental carcinogenesis when administered to pregnant rats on day 21 of timed pregnancies. None of the other 5 analogues that were tested appeared to be carcinogenic in small experiments. All the analogues which are known to have hypomethylating activity were found to be cytotoxic in vitro; the most potent being 5-azacytidine. As judged by decreased rat weight compared to untreated controls, the fluorinated cytidine analogues and 5''-deoxyazacytidine were more toxic than 5-azacytidine. Altered haemoglobin synthesis was seen in rats and DBA/2J mice, but not in sheep. In mice, where the clearest haemoglobin changes were noted, an increase in minor haemoglobin synthesis was found using both high and low doses of 5-azacytidine, and with 5,6-dihydro-5-azacytidine and 5-aza-2''-deoxycytidine. These last two analogues appear to be relatively non-toxic, noncarcinogenic in these experiments, and retain haemoglobin activating properties with a potency similar to that of 5-azacytidine.