De Pooter C M, Van Oosterom A T, Scalliet P G, Maes R A, de Bruijn E A
Laboratory of Cancer Research and Clinical Oncology, Antwerp University, Wilrijk, Belgium.
Biochem Pharmacol. 1996 Mar 8;51(5):629-34. doi: 10.1016/s0006-2952(95)02229-5.
Cis-Diamminedichloroplatinum(II) (CDDP) is used in the treatment of various cancers, with or without ionizing radiation. During treatment, resistance may develop, and cross-resistance can also occur. DNA is the main target for CDDP and ionizing radiation, and we therefore evaluated the correlation between the amount of CDDP-DNA adducts and the cytotoxic activity of CDDP in human ovarian cancer cell lines with different platinum sensitivities. DNA-adduct levels were investigated 18 hr after CDDP exposure in three cell lines originating from the same human ovarian cancer. The least sensitive cells appeared to have the largest amounts of CDDP-DNA adducts, while the most sensitive had higher adduct levels than the parental cells. The proportion of the four adducts measured (i.e., Pt-G, Pt-AG, Pt-GG, and G-Pt-G) was comparable in all cell lines, with a preference for Pt-GG adduct formation (> 50% of the adducts). Intracellular CDDP concentrations were higher in sensitive than in resistant cells, in contrast to the degree of CDDP adduct formation. Data obtained following continuous exposure of CDDP-resistant cells to CDDP suggest that DNA repair is partly responsible for resistance to CDDP. We conclude that the amount of CDDP-DNA adduct formation in cancer cells is not a predictor of CDDP cytotoxicity.
顺二氯二氨合铂（II）（CDDP）用于治疗各种癌症，无论是否联合电离辐射。在治疗过程中，可能会产生耐药性，也可能出现交叉耐药。DNA是CDDP和电离辐射的主要靶点，因此我们评估了不同铂敏感性的人卵巢癌细胞系中CDDP-DNA加合物的量与CDDP细胞毒性活性之间的相关性。在源自同一人卵巢癌的三个细胞系中，CDDP暴露18小时后研究DNA加合物水平。最不敏感的细胞似乎具有最多的CDDP-DNA加合物，而最敏感的细胞比亲代细胞具有更高的加合物水平。在所有细胞系中，所测量的四种加合物（即Pt-G、Pt-AG、Pt-GG和G-Pt-G）的比例相当，优先形成Pt-GG加合物（超过50%的加合物）。与CDDP加合物形成程度相反，敏感细胞中的细胞内CDDP浓度高于耐药细胞。将CDDP耐药细胞持续暴露于CDDP后获得的数据表明，DNA修复部分导致对CDDP的耐药性。我们得出结论，癌细胞中CDDP-DNA加合物形成的量不是CDDP细胞毒性的预测指标。
