Altered deoxyuridine and thymidine in plasma following capecitabine treatment in colorectal cancer patients.

Abstract

To investigate the relationship between changes in plasma deoxynucleoside concentrations and response and toxicity in patients treated with capecitabine. Twenty-six patients received 2 g capecitabine twice daily orally for 2 weeks of a 3-week cycle. Blood samples were collected on day 0 (baseline), day 8, day 15 and day 22 of the first cycle for the determination of plasma thymidine (TdR) and deoxyuridine (UdR) concentrations. Patients were reviewed weekly during the first cycle, then 3-weekly for toxicity assessment. Response was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. The plasma UdR and UdR/TdR ratios were significantly elevated (P < 0.001) compared with baseline (49.3 +/- 20.8 nmol l(-1)) for the entire 3-week treatment period. In contrast, the plasma TdR concentrations of these patients were significantly reduced only on day 8 (P < 0.01) compared with baseline (12.1 +/- 3.83 nmol l(-1)), but returned gradually to basal levels by day 15. There were no significant correlations demonstrated between pretreatment or maximal post-treatment plasma nucleoside ratio and either toxicity or response. The TSER genotype frequencies of homozygous TSER*2, TSER*3 and heterozygous TSER*2/*3 were 7.7%, 42.3% and 50%, respectively. These preliminary data also indicate no direct relationship between thymidylate synthase (TS) genotype and plasma nucleoside levels. Capecitabine mimics continuous infusion of 5-FU to achieve sustained cellular TS inhibitory effects and suggests the antiproliferative mechanism of capectabine is at least partly due to TS inhibition through its active metabolite FdUMP. Although plasma UdR and TdR concentrations and the UdR/TdR ratio can provide some pharmacodynamic indication of TS inhibition, they are unlikely to predict therapeutic response or toxicity accurately following capecitabine treatment in cancer patients.