Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines.
Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines.
复制标题
DOI：
--
复制
发表时间：
1997-03
期刊：
影响因子：
11.2
通讯作者：
S. Johnson;P. B. Laub;J. Beesley;R. Ozols;T. C. Hamilton
中科院分区：
文献类型：
--
作者：
S. Johnson;P. B. Laub;J. Beesley;R. Ozols;T. C. Hamilton
我们检查了一组12个不相关的人卵巢癌细胞系，这些细胞系来自未经治疗或接受铂类化疗的患者，以确定顺铂敏感性与以下因素之间是否存在关系：（a）细胞铂蓄积;（B）谷胱甘肽水平;（c）铂-DNA加合物形成;（d）铂-DNA加合物清除;和（e）铂-DNA损伤耐受性。多元回归和相关性分析显示，这些耐药机制，铂-DNA损伤耐受性与顺铂敏感性强相关（r = 0.84，P = 0.001），而铂蓄积（r = -0.11），细胞谷胱甘肽水平（r = 0.13），铂-DNA加合物清除（r = 0.44）相关性不显著。铂-DNA损伤耐受性与顺铂敏感性（IC 50）的相关性源自铂-DNA加合物形成聚类为跨越3倍范围的三个不同组，这相对于相应的43倍敏感性范围是窄的。加合物形成本身与顺铂敏感性无关（r = -0.38）。铂-DNA损伤耐受性与阿霉素（r = 0.80，P = 0.002）、紫杉醇（r = 0.87，P = 0.0002）、依托泊苷（r = 0.78，P = 0.003）和丝裂霉素C（r = 0.73，P = 0.007）的敏感性之间也存在强相关性。这些结果表明，参与识别和处理铂-DNA损伤和其他类型的药物诱导损伤（最终导致细胞死亡）的途径的失败可能导致广泛的耐药表型。
We have examined a panel of 12 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy to determine whether a relationship is present between cisplatin sensitivity and: (a) cellular platinum accumulation; (b) glutathione levels; (c) platinum-DNA adduct formation; (d) platinum-DNA adduct removal; and (e) platinum-DNA damage tolerance. Multiple regression and correlation analysis revealed that of these resistance mechanisms, platinum-DNA damage tolerance correlates strongly with cisplatin sensitivity (r = 0.84, P = 0.001), whereas platinum accumulation (r = -0.11), cellular glutathione levels (r = 0.13), and platinum-DNA adduct removal (r = 0.44) correlate insignificantly. The correlation of platinum-DNA damage tolerance to cisplatin sensitivity (IC50s) is derived from the clustering of platinum-DNA adduct formation into three distinct groups spanning a 3-fold range, which is narrow relative to the corresponding 43-fold range in sensitivity. Adduct formation itself is not associated with cisplatin sensitivity (r = -0.38). Strong correlations were also observed between platinum-DNA damage tolerance and sensitivity to Adriamycin (r = 0.80, P = 0.002), paclitaxel (r = 0.87, P = 0.0002), etoposide (r = 0.78, P = 0.003), and mitomycin C (r = 0.73, P = 0.007). These results suggest that the failure of pathways that are involved in recognizing and processing platinum-DNA damage and other types of drug-induced damage that culminate in cell death may result in a broad resistance phenotype.