Cytocidal effect and DNA damage of nedaplatin in vitro by simulating pharmacokinetic parameters

Purpose: The pharmacodynamic effects of cis-diammine(glycolato)platinum (ne daplatin, 254-S) in vitro have been reported, but the dosage and exposure t ime in vitro have not always been based on clinical observations of the dru g's actions in vivo. Regardless of the actual exposure conditions used, the effect of cell-cycle nonspecific anticancer agents such as nedaplatin is b elieved to depend on the area under the drug concentration-time curve (AUC) . In this study, we evaluated the pharmacodynamics of nedaplatin in vitro, especially in relation to its AUC dependency, in terms of cell survival and DNA crosslinking. Methods: BG-1 human ovarian cancer cells were treated wi th various concentrations of nedaplatin to simulate the pharmacokinetics of administration in a clinical setting. The BG-I cells were exposed to nedap latin dissolved in medium containing serum using constant concentration con ditions, either high (maximum 7.69 mg/l) or low (average 1.33 mg/l). These concentrations were based on doses used in clinical studies. We then adjust ed the exposure conditions in vitro to simulate the elimination of the drug from serum in vivo as follows: T-1/2 alpha 1.20 h and T-1/2 beta 2.70 h. T he AUC values were set at 4, 8, 16, 25 and 40 mg h/l for all exposure condi tions. A colony-formation assay for the surviving fraction and an alkaline- elution assay for DNA crosslink measurement were done for the pharmacodynam ic evaluation with comparison on the basis of the AUC value. Results: Expos ure to a low concentration for a long time was the most effective of the ex posure conditions at the same AUC value. The greater the AUC value, the hig her the crosslink index under all exposure conditions. This index tended to increase particularly after exposure to the low concentration. The natural logarithm of the surviving fraction (Y ') was a linear function of the cro sslink index regardless of the drug-exposure condition: ln(Y ') = -87.2x ln(5.79), R-2 = 0.89. The threshold cytocidal effect was associated with a crosslink index of 0.02. Conclusion: There was a strong correlation between the cytocidal effect of nedaplatin and DNA crosslink formation. The cytoci dal effect and DNA crosslinking in vitro depended on the exposure condition s used to define the AUG. Therefore, a new pharmacokinetic-pharmacodynamic model for nedaplatin must be constructed to investigate the most effective administration procedure in vivo.