A combined biochemical and cytogenetic study of thioridazine-induced damage to nucleic acids
A combined biochemical and cytogenetic study of thioridazine-induced damage to nucleic acids
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DOI：
10.1093/mutage/14.2.243
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发表时间：
1999-03-01
期刊：
影响因子：
2.7
通讯作者：
Lialiaris, TS
中科院分区：
文献类型：
--
作者：
Pantazaki, AA;Lialiaris, TS
在这项工作中，硫利达嗪，一种常用的吩噻嗪的生化效应，已研究后，本地双链和单链DNA，也超螺旋质粒。结果表明，硫利达嗪导致这些核酸的损伤和断裂，但仅在浓度比我们的细胞遗传学实验中使用的浓度高得多的情况下，并且损伤似乎取决于使用的浓度。此外，我们研究了硫利达嗪单独或与咖啡因和/或美法仑联合作用于体外人淋巴细胞的作用。硫利达嗪和咖啡因（一种众所周知的细胞修复机制抑制剂）显示出协同作用，以增强美法仑对人淋巴细胞的细胞遗传学效应。这表明硫利达嗪单独或与咖啡因组合，可以发挥其协同作用，对美法仑细胞毒性培养的人淋巴细胞不仅间接，即作为一个强大的钙调蛋白抑制剂，通过促进美法仑的细胞内滞留，但也直接通过与核酸反应，并通过引起剪切和损伤。因此，硫利达嗪（如氯丙嗪）具有作为治疗人类癌症的辅助化疗剂的一些潜力。
In this work the biochemical effects of thioridazine, a commonly used phenothiazine, have been studied upon native double- and single-stranded DNA and also upon a supercoiled plasmid. The results indicate that thioridazine causes damage and scissions to these nucleic acids but only at concentrations much higher than the one used in our cytogenetic experiments and that the damage seems to depend on the concentrations used. Furthermore, we studied the action of thioridazine alone or in combination with caffeine and/or melphalan upon human lymphocytes in vitro. Thioridazine and caffeine (a well-known inhibitor of cellular repair mechanisms) were shown to act synergistically to potentiate the cytogenetic effect of melphalan on human lymphocytes. It is suggested that thioridazine alone or in combination with caffeine may exert its synergistic effect on melphalan cytotoxicity to cultured human lymphocytes not only indirectly, i.e. as a strong calmodulin inhibitor by facilitating the intracellular retention of melphalan, but also directly by reaction with nucleic acids and by causing scissions in and damage to them. Therefore, thioridazine (as chlorpromazine) has some potential as an adjuvant chemotherapeutic agent for the treatment of human cancer.