Influence of cellular factors and pharmacokinetics on the formation of platinum-DNA adducts in leukocytes of children receiving cisplatin therapy

The formation of platinum (Pt)-DNA adducts is thought to be crucial to the antitumor activity of cisplatin, and relationships between adduct formation in peripheral blood leukocytes (PBLs) and response to cisplatin therapy ha ve been reported. The current study directly tests, for the first time, whe ther pharmacokinetic or other factors predominantly determine the drug-targ et interaction of cisplatin in a pediatric patient population. Cisplatin pharmacokinetics and Pt-DNA adduct formation in PBLs were determi ned in 10 children in parallel with measurement of adduct levels after incu bation of pretreatment blood samples with cisplatin in vitro. Total and unb ound plasma Pt concentrations were determined by atomic absorption spectrop hotometry and adduct measurements performed by competitive ELISA. Pt-DNA adduct levels determined after cisplatin treatment showed considerab le interindividual variation (peak levels at 24 h ranged from 0.15 to 1.31 nmol/g DNA) and correlated strongly with adduct levels determined after inc ubation of pretreatment whole blood with cisplatin (r = 0.92; P = 0.0002). No significant correlation was observed between in vivo adduct formation an d either unbound or total cisplatin plasma concentrations (r = 0.14 and 0.1 8, respectively). A correlation was also observed between the degree of mye losuppression, as determined by WBC nadirs measured over a 14-day period af ter cisplatin treatment, and the extent of adduct formation, with greater W BC toxicity observed in patients with higher levels of Pt-DNA adducts (P = 0.010). These preliminary results provide evidence that interpatient variation in f ormation of Pt-DNA adducts in PBLs of children is determined by host-specif ic factors other than cisplatin pharmacokinetics. These results imply that analysis of adducts in PBLs after incubation of pretreatment blood samples with cisplatin may be used to predict in vivo adduct levels, leukopenia, an d, potentially, response to cisplatin therapy.