cis-Diamminedichloroplatinum (II)-DNA adduct formation in renal, gonadal, and tumor tissues of male and female rats

Abstract

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.