Hah Sang Soo, Henderson Paul T, Turteltaub Kenneth W
Department of Chemistry and Research Institute for Basic Sciences, Kyung Hee University, Dongdaemun-gu, Seoul 130-701, South Korea.
Bioorg Med Chem Lett. 2010 Apr 15;20(8):2448-51. doi: 10.1016/j.bmcl.2010.03.020. Epub 2010 Mar 7.
Oxaliplatin is a third-generation platinum-based anticancer drug that is currently used in the treatment of metastatic colorectal cancer. Oxaliplatin, like other platinum-based anticancer drugs such as cisplatin and carboplatin, is known to induce apoptosis in tumor cells by binding to nuclear DNA, forming monoadducts, and intra- and interstrand diadducts. Previously, we reported an accelerator mass spectrometry (AMS) assay to measure the kinetics of oxaliplatin-induced DNA damage and repair [Hah, S. S.; Sumbad, R. A.; de Vere White, R. W.; Turteltaub, K. W.; Henderson, P. T. Chem. Res. Toxicol.2007, 20, 1745]. Here, we describe another application of AMS to the measurement of oxaliplatin-DNA adduct distribution in cultured platinum-sensitive testicular (833K) and platinum-resistant breast (MDA-MB-231) cancer cells, which resulted in elucidation of cell-dependent differentiation of oxaliplatin-DNA adduct formation, implying that differential adduction and/or accumulation of the drug in cellular DNA may be responsible for the sensitivity of cancer cells to platinum treatment. Ultimately, we hope to use this method to measure the intrinsic platinated DNA adduct repair capacity in cancer patients for use as a biomarker for diagnostics or a predictor of patient outcome.
奥沙利铂是一种第三代铂类抗癌药物，目前用于治疗转移性结直肠癌。与其他铂类抗癌药物如顺铂和卡铂一样，已知奥沙利铂通过与核DNA结合、形成单加合物以及链内和链间双加合物来诱导肿瘤细胞凋亡。此前，我们报道了一种加速器质谱（AMS）测定法，用于测量奥沙利铂诱导的DNA损伤和修复动力学[哈，S.S.；苏姆巴德，R.A.；德·韦尔·怀特，R.W.；图特尔陶布，K.W.；亨德森，P.T.《化学研究毒理学》2007年，20，1745]。在此，我们描述了AMS在测量培养的铂敏感睾丸（833K）和铂耐药乳腺（MDA-MB-231）癌细胞中奥沙利铂-DNA加合物分布方面的另一种应用，这导致了奥沙利铂-DNA加合物形成的细胞依赖性差异的阐明，这意味着药物在细胞DNA中的差异加成和/或积累可能是癌细胞对铂治疗敏感性的原因。最终，我们希望使用这种方法来测量癌症患者体内铂化DNA加合物的内在修复能力，用作诊断生物标志物或患者预后的预测指标。
