O'Neill C F, Hunakova L, Kelland L R
CRC Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey, UK.
Chem Biol Interact. 1999 Nov 15;123(1):11-29. doi: 10.1016/s0009-2797(99)00115-5.
The cellular pharmacology of two pairs of cis and trans platinum complexes has been studied in three human ovarian carcinoma cell lines, a parental relatively cisplatin-sensitive line (CH1), a subline possessing acquired cisplatin resistance (3-fold; CH1cisR) and an intrinsically cisplatin resistant line (13-fold; SKOV-3). Growth inhibition studies showed that both JM335 [trans ammine (cyclohexylaminedichloro dihydroxo) platinum(IV)] and its platinum(II) dichloro homolog JM334 were relatively less cross-resistant against both acquired and intrinsic cisplatin resistant cells. In contrast, resistance circumvention was not apparent in these cell lines with their cis isomeric counterparts (JM149 for JM335 and JM118 for JM334). The trans compound JM335 was more potent than its cis isomer against all three cell lines. There was no clear correlation between intracellular accumulation following 2 h exposure to each compound and resulting DNA platination or growth inhibition. The selective activity of the trans platinum complexes against the SKOV-3 cell line correlated with a deficiency in the repair of adducts within a fragment of the N-ras gene induced by trans compounds whereas adducts induced by the cis counterparts, and cisplatin, were repaired. The CH 1 parental line appeared repair deficient at the gene-specific level to adducts induced by both cis (including cisplatin) and trans compounds. Resistance in CH1cisR was associated with a lack of gene-specific repair of lesions formed by JM118 and JM149. All four compounds induced apoptosis in all three cell lines, as measured by fluorescent microscopy and field inverted gel electrophoresis, although the kinetics of apoptosis was markedly faster for the trans versus cis compounds. In summary, the trans platinum complexes JM335 and JM334 possess unique cellular properties compared to their cis counterparts particularly with respect to gene specific repair of DNA adducts and the rate of induction of apoptosis.
在三种人卵巢癌细胞系中研究了两对顺式和反式铂配合物的细胞药理学，这三种细胞系分别是：亲本相对顺铂敏感细胞系（CH1）、具有获得性顺铂抗性的亚系（3倍抗性；CH1cisR）和内在顺铂抗性细胞系（13倍抗性；SKOV-3）。生长抑制研究表明，JM335 [反式氨（环己胺二氯二羟基）铂（IV）]及其二氯铂（II）同系物JM334对获得性和顺铂内在抗性细胞的交叉抗性相对较小。相比之下，这些细胞系与其顺式异构体对应物（JM335对应的JM149和JM334对应的JM118）之间未明显表现出抗性逆转。反式化合物JM335对所有三种细胞系的活性均强于其顺式异构体。在接触每种化合物2小时后，细胞内积累与由此产生的DNA铂化或生长抑制之间没有明显的相关性。反式铂配合物对SKOV-3细胞系的选择性活性与反式化合物诱导的N-ras基因片段内加合物的修复缺陷相关联，而顺式对应物和顺铂诱导的加合物则被修复。CH1亲本细胞系在基因特异性水平上似乎对顺式（包括顺铂）和反式化合物诱导的加合物修复存在缺陷。CH1cisR中的抗性与JM118和JM149形成的损伤缺乏基因特异性修复有关。通过荧光显微镜和场反转凝胶电泳测量，所有四种化合物在所有三种细胞系中均诱导凋亡，尽管反式化合物诱导凋亡的动力学明显快于顺式化合物。总之，与顺式对应物相比，反式铂配合物JM335和JM334具有独特的细胞特性，特别是在DNA加合物的基因特异性修复和凋亡诱导速率方面。
