This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Veal, G. J. Articles by Tilby, M. J. Search for Related Content PubMed PubMed Citation Articles by Veal, G. J. Articles by Tilby, M. J.

Influence of Cellular Factors and Pharmacokinetics on the Formation of Platinum-DNA Adducts in Leukocytes of Children Receiving Cisplatin Therapy¹

Cancer Research Unit [G. J. V., C. D., J. E., A. V. B., D. R. N., M. J. T.] and Department of Child Health [C. D., L. P., A. P., J. H., A. D. J. P., M. J. T.], University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, United Kingdom

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 have been reported. The current study directly tests, for the first time, whether pharmacokinetic or other factors predominantly determine the drug-target interaction of cisplatin in a pediatric patient population.

Cisplatin pharmacokinetics and Pt-DNA adduct formation in PBLs were determined in 10 children in parallel with measurement of adduct levels after incubation of pretreatment blood samples with cisplatin in vitro. Total and unbound plasma Pt concentrations were determined by atomic absorption spectrophotometry and adduct measurements performed by competitive ELISA.

Pt-DNA adduct levels determined after cisplatin treatment showed considerable 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 incubation of pretreatment whole blood with cisplatin (r = 0.92; P = 0.0002). No significant correlation was observed between in vivo adduct formation and either unbound or total cisplatin plasma concentrations (r = 0.14 and 0.18, respectively). A correlation was also observed between the degree of myelosuppression, as determined by WBC nadirs measured over a 14-day period after cisplatin treatment, and the extent of adduct formation, with greater WBC toxicity observed in patients with higher levels of Pt-DNA adducts (P = 0.010).

These preliminary results provide evidence that interpatient variation in formation of Pt-DNA adducts in PBLs of children is determined by host-specific 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, and, potentially, response to cisplatin therapy.

This article has been cited by other articles:

				K. M. Darcy, C. Tian, and E. Reed A Gynecologic Oncology Group Study of Platinum-DNA Adducts and Excision Repair Cross-Complementation Group 1 Expression in Optimal, Stage III Epithelial Ovarian Cancer Treated with Platinum-Taxane Chemotherapy Cancer Res., May 1, 2007; 67(9): 4474 - 4481. [Abstract] [Full Text] [PDF]

				B. W. Cooper, G. J. Veal, T. Radivoyevitch, M. J. Tilby, H. J. Meyerson, H. M. Lazarus, O. N. Koc, R. J. Creger, G. Pearson, G. M. Nowell, et al. A Phase I and Pharmacodynamic Study of Fludarabine, Carboplatin, and Topotecan in Patients With Relapsed, Refractory, or High-Risk Acute Leukemia Clin. Cancer Res., October 15, 2004; 10(20): 6830 - 6839. [Abstract] [Full Text] [PDF]

				A.-K. Souid, R. L. Dubowy, S. M. Blaney, L. Hershon, J. Sullivan, W. D. McLeod, and M. L. Bernstein Phase I Clinical and Pharmacologic Study of Weekly Cisplatin and Irinotecan Combined with Amifostine for Refractory Solid Tumors Clin. Cancer Res., February 1, 2003; 9(2): 703 - 710. [Abstract] [Full Text] [PDF]

				W. C. Zamboni, A. C. Gervais, M. J. Egorin, J. H. M. Schellens, D. R. Hamburger, B. J. Delauter, A. Grim, E. G. Zuhowski, E. Joseph, D. Pluim, et al. Inter- and Intratumoral Disposition of Platinum in Solid Tumors after Administration of Cisplatin Clin. Cancer Res., September 1, 2002; 8(9): 2992 - 2999. [Abstract] [Full Text] [PDF]