Abstract

Background
Platinum based drugs are widely used for the treatment of various cancers, however, their efficacy is limited by the appearance of side effects and inherent or acquired drug resistance of the tumour cells. Whilst patients receive a standardised treatment regimen, based on body surface area or glomerular filtration rate, significant heterogeneity in the toxic effects and response to these agents exists. Inter-individual differences in drug responses are an important cause of resistance to treatment and adverse drug reactions. There is therefore an unmet need in oncology to develop personalised treatment regimens based on an individuals pharmacokinetic and pharmacogenetic responses.

Method
In this study the number of Pt adducts formed per DNA nucleotide has been determined in DNA samples obtained, pre- and post-infusion, from blood lymphocytes of 11 patients on different cycles of Pt-based chemotherapy. The level of adduct formation was determined by measuring the Pt/P ratio in extracted DNA using High Resolution Inductively coupled Plasma Mass Spectrometry (HR-ICP-MS).

Results
The sensitivity of the technique is such (Detection Limit:1 Pt adduct per 10⁷ nucleotides using 10 mg of DNA) that it has been possible to detect Pt-DNA adducts in samples obtained prior to the start of drug infusion in patients who have had previous cycles of Pt chemotherapy. Moreover, samples from patients who have had more chemotherapy cycles showed higher numbers of Pt adducts per nucleotide in their pre infusion samples. Initial correlation of these data with clinical notes indicates that within this very limited sample (n=11), patients with the highest Pt-DNA adducts post drug infusion have experienced more toxic effects compared to those with lower number of Pt-DNA adducts.

Conclusion
Our preliminary studies demonstrate the power of HR-ICP-MS in detecting Pt-lesions in vivo. Studies are underway to further develop the assay to increase its sensitivity and power of discrimination.