Gj. Veal et al., Influence of cellular factors and pharmacokinetics on the formation of platinum-DNA adducts in leukocytes of children receiving cisplatin therapy, CLIN CANC R, 7(8), 2001, pp. 2205-2212
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 =
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.