Pérez J M, Quiroga A G, Montero E I, Alonso C, Navarro-Ranninger C
Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Spain.
J Inorg Biochem. 1999 Apr;73(4):235-43. doi: 10.1016/s0162-0134(99)00021-5.
cis-Diamminedichloroplatinum(II) (cis-DDP) is a widely used antitumour drug which produces important damage on the DNA inducing apoptosis in several cell lines. We have analyzed the cytotoxic activity of novel cyclometallated complexes of p-isopropylbenzaldehyde thiosemicarbazone (p-is.TSCN) and their dimeric chloro-bridged derivatives in murine keratinocytes transformed by the H-ras oncogene which are resistant to cis-DDP (Pam-ras cells). The data show that, in contrast with cis-DDP, the tetrameric cycloplatinated complex [Pt(p-is.TSCN)]4 and its dimeric chloro-bridged derivative [Pt(microCl)(p-is.TSCN)]2 have a good in vitro therapeutic index when comparing the cytotoxicity in Pam-ras cells to normal murine keratinocytes (Pam 212 cells) since they induce cell death in Pam-ras cells at drug concentrations significantly lower than those needed to kill Pam 212 cells. At equitoxic doses (IC90), both complexes produce characteristic features of apoptosis in Pam-ras cells together with a drastic decrease in levels of H-ras protein. These effects are not observed when the cells are treated with the IC90 of the cis-DDP drug nor the p-is.TSCN ligand. Altogether, these results suggest that the platinum compounds [Pt(p-is.TSCN)]4 and [Pt(microCl)(p-is.TSCN)]2 might have potential as antitumour agents in view of their specific induction of apoptosis in cis-DDP resistant cells.
顺二氯二氨合铂（II）（顺铂）是一种广泛使用的抗肿瘤药物，它会对DNA造成严重损伤，从而在多种细胞系中诱导细胞凋亡。我们分析了对异丙基苯甲醛硫代半卡巴腙（对异丙基硫代半卡巴腙）的新型环金属化配合物及其二聚体氯桥联衍生物对由H-ras癌基因转化的、对顺铂耐药的小鼠角质形成细胞（Pam-ras细胞）的细胞毒性活性。数据表明，与顺铂不同，四聚体环铂配合物[Pt（对异丙基硫代半卡巴腙）]4及其二聚体氯桥联衍生物[Pt（μCl）（对异丙基硫代半卡巴腙）]2在比较Pam-ras细胞与正常小鼠角质形成细胞（Pam 212细胞）的细胞毒性时具有良好的体外治疗指数，因为它们在Pam-ras细胞中诱导细胞死亡的药物浓度明显低于杀死Pam 212细胞所需的浓度。在等毒性剂量（IC90）下，两种配合物都会在Pam-ras细胞中产生凋亡的特征性表现，同时H-ras蛋白水平会急剧下降。当用顺铂药物或对异丙基硫代半卡巴腙配体的IC90处理细胞时，不会观察到这些效应。总之，鉴于铂化合物[Pt（对异丙基硫代半卡巴腙）]4和[Pt（μCl）（对异丙基硫代半卡巴腙）]2在顺铂耐药细胞中特异性诱导凋亡，它们可能具有作为抗肿瘤药物的潜力。
