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Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

Lookup NU author(s): Dr Michael Tilby, Professor Andrew Pearson, Professor Alan Boddy, Professor Herbie Newell


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Platinum (Pt)-DNA adducts were measured in peripheral blood leucocytes (PBLs) from 24 children with solid tumours after standard cisplatin and/or carboplatin treatment. The relationship between Pt-DNA adduct levels and pharmacokinetics of cisplatin and carboplatin was investigated. Adduct measurements were performed by competitive enzyme-linked immunosorbent assay (ELISA) and plasma unbound Pt concentrations were measured by atomic absorption spectrophotometry (AAS). There was considerable interindividual variation in Pt-DNA adduct level that was weakly correlated (r2 = 0.32) with the area under the unbound drug concentration vs time curve (AUC) at 6 h after the start of cisplatin infusion, indicating that the variation in Pt-DNA adduct levels was primarily determined by factors other than AUC. No clear relationship between AUC and adduct levels was seen at 24 and 48 h after cisplatin or at 6, 24 or 48 h after carboplatin. Carboplatin produced lower levels of immunoreactive adducts than did cisplatin (1.3 ± 0.6 nmol Pt g-1 DNA vs 3.2 ± 1.7 nmol Pt g-1 DNA), despite a 20-fold higher unbound drug AUC for carboplatin (8.0 ± 3.5 mg ml-1 min vs 0.4 ± 0.2 mg ml-1 min). This study demonstrates that, after cisplatin and carboplatin treatment the drug-target interaction is determined by both pharmacokinetic and, predominantly, cellular factors. Intrinsic differences between the two complexes, primarily reactivity, probably explain the lower adduct levels observed after carboplatin treatment.

Publication metadata

Author(s): Peng, B., Tilby, M. J., English, M., Price, L., Pearson, A. D. J., Boddy, A. V., Newell, D. R.

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 1997

Volume: 76

Issue: 11

Pages: 1466-1473

ISSN (print): 0007-0920

ISSN (electronic):


PubMed id: 9400943