Deoxyuridine as a surrogate marker of thymidylate synthase inhibition contributes to a multivariable model predicting 5-FU/LV response in metastatic colorectal cancer.

[BACKGROUND] Colorectal cancer (CRC) chemotherapy is based on 5-fluorouracil (5-FU) and the folate leucovorin (LV). The active metabolites of these compounds, 5-fluorodeoxyuridine monophosphate (FdUMP) and 5,10-methylenetetrahydrofolate (5,10-MeTHF), form an inhibitory complex with thymidylate synthase (TS) resulting in elevated deoxyuridine (dUr) levels. In contrast to LV, natural 5,10-MeTHF (arfolitixorin, ARF) participates directly in the complex. Pyridoxal 5'-phosphate (PLP) potentially boosts 5-FU/LV (FLV)-based chemotherapy.

[OBJECTIVE] The study explored the correlation between dUr levels in tumor homogenates and tumor response, and assessed the impact of LV and ARF, combined with FdUMP and optionally PLP, on dUr levels.

[PATIENTS AND METHODS] Sixty-seven patients with metastatic CRC receiving first-line FLV-based chemotherapy and exhibiting either tumor response or disease progression were included. Tumor homogenates were prepared from snap-frozen primary tumors, and the dUr level was analyzed using LC-MS/MS. Fit modelling was used to predict the effect of explanatory variables on tumor response.

[RESULTS] Significantly higher dUr levels were observed after the addition of ARF compared to LV. dUr levels correlated positively with ARF, but not with LV, dosage. Adding PLP to LV increased dUr levels in 43% of homogenates but levels remained lower than those achieved with ARF alone. The baseline dUr level, together with the variables tumor location, BMI, and chemotherapy regimen were predictive for tumor response.

[CONCLUSIONS] The method used enables simultaneous analysis of multiple compounds within a tumor homogenate. Measuring dUr in homogenates before and after folate modulation, prior to initiation of FLV-based chemotherapy, could help predict tumor response and guide the choice between LV and ARF for optimal folate support.