Oxidative damage to guanine nucleosides following combination chemotherapy with 5-fluorouracil and oxaliplatin

Recent in vitro and animal studies have suggested that the cytotoxicity of 5-fluorouracil and oxaliplatin is linked to increased formation of reactive oxygen species (ROS). This prospective study was undertaken to examine the generation of oxidative stress, in 106 colorectal cancer patients, by 5-fluorouracil and oxaliplatin combination (FOLFOX) therapy as measured by urinary excretion of 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydro-guanosine (8-oxoGuo). The amounts of 8-oxoGuo and 8-oxodG were measured in 3 spot urine samples from 106 patients by using ultra performance liquid chromatography and tandem mass spectrometry. Furthermore, we collected information on other clinical and demographic variables hypothesized to be associated with oxidative stress. Repeated measures linear mixed models were used to model the relationship between urinary concentrations of 8-oxoGuo and 8-oxodG and the treatment effect and the other variables. The analysis showed that chemotherapy increased the excretion of 8-oxoGuo and 8-oxodG around 15% (P < 0.0001 and P = 0.02, respectively) though there was a significant interaction with CRP levels. Additionally, we found that sex, smoking status, age, and c-reactive protein were related to urinary excretion of 8-oxoGuo and 8-oxodG in colorectal cancer patients. These results indicate that FOLFOX induces ROS in patients and that ROS-generating mechanisms interact.