Anti-proliferative activity and mechanism of action of titanocene dichloride.
Anti-proliferative activity and mechanism of action of titanocene dichloride.
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DOI：
10.1038/bjc.1998.352
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发表时间：
1998-06
影响因子：
8.8
通讯作者：
Kerr, D J
中科院分区：
文献类型：
--
作者：
Christodoulou, C V;Eliopoulos, A G;Young, L S;Hodgkins, L;Ferry, D R;Kerr, D J
对细胞毒性药物产生耐药性是其临床应用的主要限制。合成新化合物的目的是开发非交叉耐药性、毒性更小和更有效的活性。无机化合物顺铂的抗肿瘤特性的检测激发了对其他含金属配合物的广泛研究。在此基础上合成了二氯化二茂钛，并在实验动物中显示出有效的抗肿瘤活性。我们检测了二氯化二茂钛在两对铂敏感和耐药的人卵巢癌细胞系 A2780/2780CP 和 CH1/CH1cisR 以及突变的 p53 和 bcl-2 转染的 A2780 细胞克隆中的体外活性。在用二氯化二茂钛处理的所有细胞系中观察到时间和浓度依赖性的抗增殖作用。该药物被发现能显着克服 2780CP 和 CH1 cisR 细胞系以及 A2780 细胞的 bcl-2 和突变 p53 转染子中的铂耐药性。二氯化二茂钛诱导细胞周期 S 晚期/G2 早期阻断；然而，细胞凋亡发生在周期的任何阶段。使用原子吸收光谱法在用二氯化二茂钛处理的 A2780 细胞中检测到钛-DNA 加合物，表明 DNA 可能是该药物的靶标。与这一发现一致的是，p53 在药物处理的 A2780 细胞中迅速积累，表明二氯化二茂钛作为 DNA 损伤剂的作用。我们还进行了研究，以确定二氯化二茂钛是否可以在体外表现出与其他细胞毒性药物的协同作用。获得的细胞毒性数据的等效线图分析表明二氯化二茂钛和5-氟尿嘧啶(5-FU)的组合具有协同作用。该化合物具有强大的体内抗肿瘤活性，并得到两项 I 期临床试验令人鼓舞的结果的支持，表明二氯化二茂钛可能是一种有前途的新型化疗剂。
Development of resistance to cytotoxic agents is a major limitation to their clinical use. Novel compounds are synthesized with a view to develop non-cross-resistant, less toxic and more potent activity. The detection of the anti-tumour properties of the inorganic compound cisplatin stimulated a broad search for other metal-containing complexes. Titanocene dichloride was synthesized on this basis and has shown potent anti-neoplastic activity in experimental animals. We have examined the in vitro activity of titanocene dichloride in two pairs of platinum-sensitive and resistant human ovarian carcinoma cell lines, A2780/2780CP and CH1/CH1cisR, and in mutated p53- and bcl-2-transfected clones of A2780 cells. A time- and concentration-dependent anti-proliferative effect was observed in all cell lines treated with titanocene dichloride. The drug was found to significantly overcome platinum resistance in the 2780CP and the CH1 cisR cell lines and in the bcl-2 and the mutant p53 transfectants of A2780 cells. Titanocene dichloride induced a block in late S/early G2 phase of the cell cycle; however apoptotic cell death occurred from any phase of cycle. Titanium-DNA adducts were detected in A2780 cells treated with titanocene dichloride using atomic absorption spectrometry, suggesting that DNA may be a target for this drug. In agreement with this finding, p53 accumulated rapidly in drug-treated A2780 cells, indicative of a role for titanocene dichloride as a DNA-damaging agent. We have also performed studies to determine whether titanocene dichloride could demonstrate synergy with other cytotoxic agents in vitro. Isobologram analysis of cytotoxicity data obtained suggests that the combination of titanocene dichloride and 5-fluorouracil (5-FU) is synergistic. The potent in vivo anti-tumour activity of this compound, supported by the encouraging results from two phase I clinical trials, suggests that titanocene dichloride could be a promising novel chemotherapeutic agent.