Therapy-induced carboplatin-DNA adduct levels in human ovarian tumours in relation to assessment of adduct measurement in mouse tissues

Jarvis, I.W.H.; Meczes, E.L.; Thomas, H.D.; Edmondson, R.J.; Veal, G.J.; Boddy, A.V.; Ottley, C.J.; Pearson, D.G.; Tilby, M.J.

Abstract

Despite an increasing understanding of the molecular mechanisms by which platinum drug DNA adducts interact with cellular processes, the relationship between adduct formation in tumours and clinical response remains unclear. We have determined carboplatin–DNA adduct levels in biopsies removed from ovarian cancer patients following treatment. Reliability of DNA adduct measurements in tissues samples were assessed using experimental animals. Platinum–DNA adduct levels were measured using inductively coupled plasma mass spectrometry (ICP-MS) and plasma drug concentrations determined by atomic absorption spectrometry (AAS). Adduct levels in tissues and plasma pharmacokinetics were determined in Balb/c mice exposed to platinum drugs. Comparisons of adduct levels in tumour and normal tissue were made in nu/nu mice carrying human neuroblastoma xenografts. At 30 min post-cisplatin administration, adduct levels in DNA from kidney and liver were approximately 10- and 6-fold higher than spleen or tumour. By 60 min, levels in liver and kidney, but not spleen or tumour, had fallen considerably. Carboplatin showed high adduct levels only in kidney. Adduct levels in tumour xenografts were comparable to those induced in vitro with similar drug exposures. In clinical samples removed 6 h after drug administration, adduct levels ranged from 1.9 to 4.3 and 0.2 to 3.6 nmol Pt/g DNA for tumour biopsies and peripheral blood mononuclear cells, respectively. No correlation was apparent between these two data sets. The present results demonstrate that reliable measurements of adducts in clinical tumours are feasible. Future results should provide insight into drug resistance.

• Journal Article Type: Article
• Acceptance Date: Oct 4, 2011
• Online Publication Date: Oct 14, 2011
• Publication Date: 2012-01
• Deposit Date: Jan 20, 2012
• Journal: Biochemical Pharmacology
• Print ISSN: 0006-2952
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 83
• Issue: 1
• Pages: 69-77
• DOI: https://doi.org/10.1016/j.bcp.2011.10.005
• Public URL: https://durham-repository.worktribe.com/output/1499031