Effect of cisplatin on cell death and DNA crosslinking in rat mammary adenocarcinoma in vitro

The pharmacodynamic effects of cis-diamminedichloroplatinum(II) (CDDP) in v itro have been reported, but the dosage and exposure time in vitro have not been based on clinical observations of the drug's actions in vivo. In this study, the authors attempted to evaluate the pharmacodynamic effects of CD DP in vitro in terms of cell survival and DNA crosslinking by simulating un bound CDDP administration at varying concentrations to a rat mammary adenoc arcinoma line (known as line 66). CDDP exposure was conducted by both const ant concentration procedures and a simulated in vivo procedure. Colony form ation assay for the surviving fraction and alkaline elution assay for DNA c rosslink measurement were performed in order to evaluate the pharmacodynami cs of CDDP. Cell survival was a function of the area under the drug concent ration time curve (AUC) of unbound CDDP (R-2 = 0.77, P < 0.002) for all dru g exposure procedures as analyzed by the analysis of covariance test. There was a strong correlation between the surviving fraction and the crosslink index of the total amount of DNA crosslinks (R-2 = 0.85, P < 0.0005), Both the total amount of DMA-DNA crosslinks and the DNA-protein crosslinks, of w hich the latter were dominant, were affected not by the exposure procedures , but by the AUC value (P < 0.002). The thresholds of cytocidal effect were 1.59 mg.h/l for the AUC and 0.008 for the crosslink index. The pharmacodyn amic effects in vitro by simulated in vivo exposure were identical to those of constant.