Pérez José M, Kelland Lloyd R, Montero Eva I, Boxall Frances E, Fuertes Miguel A, Alonso Carlos, Navarro-Ranninger Carmen
Departamento de Química Inorgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.
Mol Pharmacol. 2003 Apr;63(4):933-44. doi: 10.1124/mol.63.4.933.
The antitumor and cellular pharmacological properties of the trans-Pt(IV) complex, trans-[PtCl(2)(OH)(2)(dimethylamine)(isopropylamine)] (compound 2) has been evaluated in comparison with its corresponding trans-Pt(II) counterpart, trans-[PtCl(2)(dimethylamine)(isopropylamine)] (compound 1). The results reported here indicate that compound 2 markedly circumvents cisplatin resistance in 41McisR and CH1cisR ovarian tumor cell lines endowed with different mechanisms of resistance (decreased platinum accumulation and enhanced DNA repair/tolerance, respectively). However, compound 1 is able to circumvent cisplatin resistance only in CH1cisR cells. Interestingly, at equitoxic concentrations, compounds 1 and 2 induce a higher amount of apoptotic cells than cisplatin in CH1cisR cells. Moreover, the number of apoptotic cells induced by compounds 1 and 2 correlates with their ability to form DNA interstrand cross-links in CH1cisR cells. Although compounds 1 and 2 showed remarkable cytotoxic activity, only compound 2 was able to inhibit the growth of CH1 human ovarian carcinoma xenografts in mice. Binding studies with serum albumin indicate that compound 1 possesses a much higher reactivity against albumin than compound 2. Moreover, the level of binding of compound 1 to plasma proteins during the period 15 min to 1 h after administration to mice (15 mg/kg, i.p.) is 2.5-fold higher than that of compound 2. Therefore, the lack of in vivo antitumor activity shown by compound 1 might be related to its extracellular inactivation before reaching the tumor site because of its high rate of binding to plasma proteins.
已对反式 - Pt(IV) 配合物反式 - [PtCl₂(OH)₂(二甲胺)(异丙胺)]（化合物 2）及其相应的反式 - Pt(II) 类似物反式 - [PtCl₂(二甲胺)(异丙胺)]（化合物 1）的抗肿瘤和细胞药理学特性进行了评估比较。此处报告的结果表明，化合物 2 能显著克服 41McisR 和 CH1cisR 卵巢肿瘤细胞系中的顺铂耐药性，这两种细胞系具有不同的耐药机制（分别为铂积累减少和 DNA 修复/耐受性增强）。然而，化合物 1 仅能克服 CH1cisR 细胞中的顺铂耐药性。有趣的是，在等毒性浓度下，化合物 1 和 2 在 CH1cisR 细胞中诱导凋亡细胞的数量比顺铂更多。此外，化合物 1 和 2 诱导的凋亡细胞数量与其在 CH1cisR 细胞中形成 DNA 链间交联的能力相关。尽管化合物 1 和 2 显示出显著的细胞毒性活性，但只有化合物 2 能够抑制小鼠体内 CH1 人卵巢癌异种移植瘤的生长。与血清白蛋白的结合研究表明，化合物 1 对白蛋白的反应性比化合物 2 高得多。此外，给小鼠腹腔注射（15 mg/kg）后 15 分钟至 1 小时期间，化合物 1 与血浆蛋白的结合水平比化合物 2 高 2.5 倍。因此，化合物 1 缺乏体内抗肿瘤活性可能与其在到达肿瘤部位之前由于与血浆蛋白的高结合率而发生细胞外失活有关。
