Le Pla Rachel C, Ritchie Kenneth J, Henderson Colin J, Wolf C Roland, Harrington Chris F, Farmer Peter B
Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, University Road, Leicester, U.K.
Chem Res Toxicol. 2007 Aug;20(8):1177-82. doi: 10.1021/tx700088j. Epub 2007 Jul 18.
Cellular resistance, both intrinsic and acquired, poses a problem in the effectiveness of platinum-based chemotherapy. The cytotoxic activity of Pt-based chemotherapeutic agents is derived from their ability to react with cellular DNA. Oxaliplatin binds to the N7 position of the purine DNA bases, forming mainly intrastrand cross-links between either two adjacent guanines (GG), an adjacent adenine and guanine (AG), or two guanines separated by an unmodified nucleotide (GNG). We report the development of a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method for measuring GG and AG intrastrand cross-links formed by oxaliplatin. The limits of detection for GG-oxPt and AG-oxPt were 23 and 19 adducts per 10 (8) nucleotides, respectively. We compare the formation and persistence of intrastrand cross-links between wild-type and glutathione transferase P null mice (GSTP null) treated with oxaliplatin. No significant difference was observed in the level of intrastrand cross-links formed by oxaliplatin between the mouse strains in liver, kidney, and lung DNA. Adduct levels were greatest in liver and lowest in lung tissue.
细胞耐药性，包括内在耐药性和获得性耐药性，给铂类化疗的有效性带来了问题。铂类化疗药物的细胞毒性活性源于它们与细胞DNA反应的能力。奥沙利铂与嘌呤DNA碱基的N7位结合，主要在两个相邻鸟嘌呤（GG）、相邻腺嘌呤和鸟嘌呤（AG）或被未修饰核苷酸隔开的两个鸟嘌呤（GNG）之间形成链内交联。我们报告了一种用于测量奥沙利铂形成的GG和AG链内交联的液相色谱 - 电喷雾电离串联质谱（LC - ESI - MS/MS）方法的开发。GG - oxPt和AG - oxPt的检测限分别为每10（8）个核苷酸23和19个加合物。我们比较了用奥沙利铂处理的野生型和谷胱甘肽转移酶P基因敲除小鼠（GSTP基因敲除）之间链内交联的形成和持久性。在肝、肾和肺DNA中，两种小鼠品系之间由奥沙利铂形成的链内交联水平未观察到显著差异。加合物水平在肝脏中最高，在肺组织中最低。
