Stopper H, Körber C, Gibis P, Spencer D L, Caspary W J
Institute of Pharmacology and Toxicology, University of Würzburg, Germany.
Carcinogenesis. 1995 Jul;16(7):1647-50. doi: 10.1093/carcin/16.7.1647.
Jones and coworkers demonstrated a qualitative correlation between 5-azacytidine and some of its analogs in inducing changes in cell morphology and their ability in preventing DNA methylation. Previously, we evaluated the same compounds to determine their ability to induce trifluorothymidine (TFT) resistance in L5178Y mouse cells and found that their mutagenic potency also correlated with their reported ability to induce morphological changes in C3H10T1/2 cells. Here, we examine four of the same analogs, 5-fluoro-2'-deoxycytidine, 5-azacytidine, 5,6-dihydro-5-azacytidine and 6-azacytidine, to find out if micronuclei induced by these compounds correlated with these effects. The most cytotoxic analog was 5-fluoro-2'-deoxycytidine, followed by 5-azacytidine. 5,6-Dihydro-5-azacytidine and 6-azacytidine were substantially less cytotoxic. All four compounds induced micronuclei. The lowest dose ranges at which responses were observed for micronucleus induction were -0.04 microM for 5-fluoro-2'-deoxycytidine, 0.2 microM for 5-azacytidine and 10-20 microM for 5,6-dihydro-5-azacytidine and 6-azacytidine. Lack of kinetochore staining in most of the micronuclei indicated that all four compounds were clastogenic. We note a general trend in the biological activity of these analogs: compounds that are specifically blocked at the 5 position such as 5-azacytidine and 5-fluoro-2'-deoxycytidine effect changes in cell morphology, cytotoxicity, TFT resistance and the induction of micronuclei at very low doses. 5-Azacytidine analogs that possess more chemically accessible 5 positions such as 5,6-dihydro-5-azacytidine and 6-azacytidine either require doses that are orders of magnitude greater to induce these effects or are unable to induce changes in cell morphology and TFT resistance at doses below which the compound is lethal to the cells.
琼斯及其同事证明了5-氮杂胞苷及其一些类似物在诱导细胞形态变化和防止DNA甲基化能力之间存在定性相关性。此前，我们评估了相同的化合物，以确定它们在L5178Y小鼠细胞中诱导三氟胸苷（TFT）抗性的能力，发现它们的诱变效力也与它们报道的在C3H10T1/2细胞中诱导形态变化的能力相关。在此，我们研究了四种相同的类似物，即5-氟-2'-脱氧胞苷、5-氮杂胞苷、5,6-二氢-5-氮杂胞苷和6-氮杂胞苷，以确定这些化合物诱导的微核是否与这些效应相关。细胞毒性最大的类似物是5-氟-2'-脱氧胞苷，其次是5-氮杂胞苷。5,6-二氢-5-氮杂胞苷和6-氮杂胞苷的细胞毒性要小得多。所有四种化合物均诱导了微核。观察到微核诱导反应的最低剂量范围分别为：5-氟-2'-脱氧胞苷为0.04微摩尔，5-氮杂胞苷为0.2微摩尔，5,6-二氢-5-氮杂胞苷和6-氮杂胞苷为10 - 20微摩尔。大多数微核中缺乏动粒染色表明所有四种化合物都具有断裂剂作用。我们注意到这些类似物的生物活性存在一个总体趋势：在5位被特异性阻断的化合物，如5-氮杂胞苷和5-氟-2'-脱氧胞苷，在非常低的剂量下就能影响细胞形态、细胞毒性、TFT抗性和微核的诱导。具有更易于化学修饰的5位的5-氮杂胞苷类似物，如5,6-二氢-5-氮杂胞苷和6-氮杂胞苷，要么需要高出几个数量级的剂量才能诱导这些效应，要么在低于化合物对细胞致死剂量时无法诱导细胞形态和TFT抗性的变化。
