Mellish K J, Kelland L R, Harrap K R
Drug Development Section, Institute of Cancer Research, Sutton, Surrey, UK.
Br J Cancer. 1993 Aug;68(2):240-50. doi: 10.1038/bjc.1993.322.
The platinum drug chemosensitivity of five human cervical squamous cell carcinoma cell lines (HX/151, HX/155, HX/156, HX/160 and HX/171) derived from previously untreated patients has been determined. Compared to our data obtained previously using human ovarian carcinoma cell lines, all five lines were relatively resistant to cisplatin, carboplatin, iproplatin and tetraplatin. One of the lines (HX/156) was exceptionally sensitive to the novel platinum (IV) ammine/amine dicarboxylates JM216 [bis-acetatoammine dichloro (cyclohexylamine) platinum (IV)] and JM221 [ammine dibutyrato dichloro (cyclohexylamine) platinum (IV)]. The range in IC50 values across the five lines was approximately 2.5-fold for cisplatin, carboplatin and iproplatin, 13-fold for tetraplatin and JM216, and 25-fold for JM221. No significant correlation (P > 0.05) was observed between platinum drug chemosensitivity and either glutathione levels or cadmium chloride sensitivity, an indicator of metallothionein levels. In addition, there was no significant correlation (P > 0.05) between cisplatin cytotoxicity and intracellular cisplatin accumulation or JM216 cytotoxicity and intracellular JM216 accumulation over the dose range 5-100 microM (2 h exposure). The exceptional sensitivity of HX/156 to JM216 appears, at least partially, to be a result of enhanced accumulation of JM216. An 8.6-fold acquired cisplatin resistant stable variant of HX/155 has been generated in vitro. Intracellular cisplatin accumulation was reduced by 2.4 +/- 0.3-fold (mean +/- s.d.) in HX/155cisR across the dose range 1-100 microM (2 h exposure). Glutathione levels in HX/155cisR were elevated by 1.3-fold in terms of protein content and by 1.6-fold in terms of cell number. HX/155cisR was 1.9-fold resistant to cadmium chloride. Total platinum bound to DNA after cisplatin exposure (10, 25, 50 or 100 microM for 2 h) was 3.6 +/- 0.6-fold (mean +/- s.d.) lower in HX/155cisR. Hence the mechanism of acquired cisplatin resistance in HX/155cisR appears to be multifocal, with reduced intracellular drug accumulation and elevated glutathione and metallothionein levels combining to reduce DNA platination levels. While HX/155cisR was cross-resistant to tetraplatin and carboplatin, novel platinum (II) and (IV) ammine/amine complexes, including JM216 and JM221, partially circumvented resistance (resistance factors of 1.5-2). Non cross-resistance was observed to iproplatin and nine non-platinum anticancer agents. Intracellular tetraplatin accumulation was reduced by 1.8 +/- 0.1-fold (mean +/- s.d.) in HX/155cisR across the dose range 1-100 microM (2 h exposure). In contrast, after JM216 exposure (1-100 microM for 2 h), no significant difference in intracellular platinum levels between HX/155 and HX/155cisR was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
已测定了来自未经治疗患者的5种人宫颈鳞状细胞癌细胞系（HX/151、HX/155、HX/156、HX/160和HX/171）对铂类药物的化学敏感性。与我们之前使用人卵巢癌细胞系获得的数据相比，所有这5种细胞系对顺铂、卡铂、异丙铂和四铂相对耐药。其中一种细胞系（HX/156）对新型铂（IV）氨/胺二羧酸盐JM216 [双乙酸氨二氯（环己胺）铂（IV）]和JM221 [氨二丁酸二氯（环己胺）铂（IV）]异常敏感。5种细胞系中顺铂、卡铂和异丙铂的IC50值范围约为2.5倍，四铂和JM216为13倍，JM221为25倍。未观察到铂类药物化学敏感性与谷胱甘肽水平或氯化镉敏感性（金属硫蛋白水平的指标）之间存在显著相关性（P>0.05）。此外，在5 - 100 microM剂量范围（暴露2小时）内，顺铂细胞毒性与细胞内顺铂积累之间或JM216细胞毒性与细胞内JM216积累之间均无显著相关性（P>0.05）。HX/156对JM216的异常敏感性似乎至少部分是由于JM216积累增加所致。已在体外产生了HX/155的一种8.6倍获得性顺铂耐药稳定变体。在1 - 100 microM剂量范围（暴露2小时）内，HX/155cisR中的细胞内顺铂积累降低了2.4±0.3倍（平均值±标准差）。HX/155cisR中的谷胱甘肽水平按蛋白质含量升高了1.3倍，按细胞数量升高了1.6倍。HX/155cisR对氯化镉耐药1.9倍。顺铂暴露（10、25、50或100 microM，2小时）后与DNA结合的总铂在HX/155cisR中降低了3.6±0.6倍（平均值±标准差）。因此，HX/155cisR中获得性顺铂耐药的机制似乎是多方面的，细胞内药物积累减少以及谷胱甘肽和金属硫蛋白水平升高共同导致DNA铂化水平降低。虽然HX/155cisR对四铂和卡铂有交叉耐药性，但新型铂（II）和（IV）氨/胺配合物，包括JM216和JM221，部分克服了耐药性（耐药因子为1.5 - 2）。未观察到对异丙铂和9种非铂类抗癌药物的交叉耐药性。在1 - 100 microM剂量范围（暴露2小时）内，HX/155cisR中的细胞内四铂积累降低了1.8±0.1倍（平均值±标准差）。相比之下，JM216暴露（1 - 100 microM，2小时）后，未观察到HX/
