Reed E, Litterst C L, Thill C C, Yuspa S H, Poirier M C
Cancer Res. 1987 Feb 1;47(3):718-22.
cis-Diamminedichloroplatinum(II) (cisplatin), a potent anticancer agent, is thought to exert its cytotoxic effects through DNA damage. Using a polyclonal rabbit antisera which recognizes intrastrand bidentate deoxy(ApG)- and deoxy(GpG)-N7-diammineplatinum adducts, an enzyme-linked immunosorbent assay has been developed to quantitate this adduct in cisplatin-exposed DNA. Cisplatin-DNA adducts were measured in renal, gonadal, and tumor (sarcoma) tissues of Sprague-Dawley rats following i.v. or i.p. administration of cisplatin. When drug was administered i.v. to animals fed ad libitum adduct levels were highest in kidneys, 50% lower in s.c. sarcoma, and substantially lower in gonads. Under these experimental conditions, a large interindividual variability in adduct formation was observed in renal and tumor tissues, and adduct levels in some samples were too low to measure. Higher values among individuals were obtained using tissues of animals fasted overnight and treated i.p. Adduct levels following i.p. injections of drug were higher in kidneys and gonads of male rats than in kidneys and gonads of female rats. Analysis of tissue platinum content demonstrated higher platinum levels in kidneys of male rats than in kidneys of female rats, but the magnitude of this gender difference in total tissue platinum was not as great as that observed for adduct formation. When the influence of castration on adduct formation was investigated, adduct levels in kidneys of castrated females were higher than those in sham-operated females, but adduct levels in kidneys of the castrated male animals were not substantively different from those seen in sham-operated male controls. We conclude that the route of drug administration, diet, and hormonal status of the animal are factors that may influence cisplatin-DNA adduct formation in the rat.
顺二氯二氨合铂（II）（顺铂）是一种强效抗癌剂，被认为通过DNA损伤发挥其细胞毒性作用。利用一种能识别链内双齿脱氧（ApG）-和脱氧（GpG）-N7-二氨铂加合物的多克隆兔抗血清，开发了一种酶联免疫吸附测定法来定量顺铂处理的DNA中的这种加合物。在静脉内或腹腔内给予顺铂后，测定了Sprague-Dawley大鼠的肾、性腺和肿瘤（肉瘤）组织中的顺铂-DNA加合物。当对自由采食的动物静脉内给药时，加合物水平在肾脏中最高，在皮下肉瘤中低50%，在性腺中则低得多。在这些实验条件下，在肾和肿瘤组织中观察到加合物形成存在很大的个体间差异，并且一些样品中的加合物水平过低无法测量。使用过夜禁食并经腹腔内处理的动物的组织，个体间获得了更高的值。腹腔内注射药物后，雄性大鼠肾和性腺中的加合物水平高于雌性大鼠肾和性腺中的加合物水平。组织铂含量分析表明，雄性大鼠肾脏中的铂水平高于雌性大鼠肾脏中的铂水平，但这种性别差异在总组织铂中的幅度不如加合物形成中观察到的那么大。当研究去势对加合物形成的影响时，去势雌性大鼠肾脏中的加合物水平高于假手术雌性大鼠，但去势雄性动物肾脏中的加合物水平与假手术雄性对照中观察到的没有实质性差异。我们得出结论，药物给药途径、饮食和动物的激素状态是可能影响大鼠顺铂-DNA加合物形成的因素。
