Lanzi C, Perego P, Supino R, Romanelli S, Pensa T, Carenini N, Viano I, Colangelo D, Leone R, Apostoli P, Cassinelli G, Gambetta R A, Zunino F
Oncologia Sperimentale B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Biochem Pharmacol. 1998 Apr 15;55(8):1247-54. doi: 10.1016/s0006-2952(97)00599-6.
In an attempt to examine the cellular changes associated with cisplatin resistance, we selected a cisplatin-resistant (A43 1/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellular defence systems and other cellular factors probably involved in dealing with cisplatin-induced DNA damage. Resistant cells exhibited decreased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. Analysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G2M arrest in sensitive and resistant cells. Interestingly, a slowdown in S-phase transit was found in A431/Pt cells. A comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to tolerate higher levels of cisplatin-induced DNA damage than their parental counterparts. Analysis of the expression of proteins involved in DNA mismatch repair showed a decreased level of MSH2 in resistant cells. Since MSH2 seems to be involved in recognition of drug-induced DNA damage, this change may account for the increased tolerance to DNA damage observed in the resistant subline. In conclusion, the involvement of accumulation defects and the increased tolerance to cisplatin-induced DNA damage in these cisplatin-resistant cells support the notion that multiple changes contribute to confer a low level of cisplatin resistance.
为了研究与顺铂耐药相关的细胞变化，我们在体外持续药物暴露后选择了一种顺铂耐药（A431/Pt）人宫颈鳞状细胞癌细胞系。该耐药亚系的耐药程度为2.5倍。具体而言，我们研究了细胞防御系统以及其他可能参与应对顺铂诱导的DNA损伤的细胞因子的表达。短期药物暴露后，耐药细胞的铂积累减少，DNA结合铂水平降低，链间交联频率降低。对顺铂对细胞周期进程影响的分析显示，顺铂在敏感细胞和耐药细胞中均诱导G2M期阻滞。有趣的是，在A431/Pt细胞中发现S期进程放缓。对敏感细胞和耐药细胞修复药物诱导的DNA损伤能力的比较表明，耐药细胞比其亲代细胞能够耐受更高水平的顺铂诱导的DNA损伤。对参与DNA错配修复的蛋白质表达的分析显示，耐药细胞中MSH2水平降低。由于MSH2似乎参与药物诱导的DNA损伤的识别，这种变化可能解释了在耐药亚系中观察到的对DNA损伤耐受性增加的现象。总之，这些顺铂耐药细胞中积累缺陷的参与以及对顺铂诱导的DNA损伤耐受性的增加支持了多种变化导致低水平顺铂耐药的观点。
