Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

Abstract

In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m(-2) oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials.

Figure 1

Mean platinum concentration-time profiles (mean±s.d.; n=37) in plasma (•) and ultrafiltrate (○).

Figure 2

Individual and median platinum-nucleotide ratios (n=37); (A) of nonresponders (•) and responders (○); (B) of patients with low (0–1; •) and high (2–4; ○) grade of neurotoxicity.

Figure 3

Relationship between area under the platinum-nucleotide adduct curve (AUA_0−48 h) and AUC_0−48 h in ultrafiltrate (A) and plasma (B).

Figure 4

Individual and median platinum-nucleotide area under the adduct curve (AUA_0–48 h); (A) of nonresponders (n=23) and responders (n=5); (B) of patients with low (0–1; n=9) and high (2–4; n=24) grade of neurotoxicity.

Figure 5

Individual and median maximum platinum-nucleotide ratio (A_max); (A) of nonresponders (n=26) and responders (n=5); (B) of patients with low (0–1; n=9) and high (2–4; n=28) grade of neurotoxicity.