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

Abstract

AimsTo investigate the relationship between changes in plasma deoxynucleoside concentrations and response and toxicity in patients treated with capecitabine. MethodsTwenty-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. ResultsThe 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. ConclusionsCapecitabine 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.

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

“…Firstly, plasma dUrd concentrations may not be sensitive indicators of TS inhibition. However, in a previous study of capecitabine we saw protracted elevation of plasma dUrd concentrations that lasted for the entire course of treatment (Li et al, 2007). An alternative explanation is that inhibition of TS by folate-based agents is not durable, in spite of intracellular polyglutamation, and can be competed out by naturally occurring folates once plasma drug levels are reduced.…”

Incorporation of guanosine gels into sieving matrices for length‐ and sequence‐based separation of DNA in capillary electrophoresis

“…Experiments with perfused rat heart have not identified any de novo synthesis of deoxyribonucleosides in mitochondria,91 questioning whether mitochondrial salvage enzymes can be considered inadequate across all tissue types. Moreover, the model has been constructed by considering a constant nucleoside concentration of 0.5 µM,92 a level that is 50‐fold lower than estimates found in the literature93 and one that leads to a conclusion that the salvage pathway plays a minimal role in mtDNA synthesis in all tissues. These examples illustrate the impact of tissue‐specific differences in biological pathways that can limit the generalizability of the model to other species or cell and tissue types.…”

Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphisms and Toxicity to Capecitabine in Advanced Colorectal Cancer Patients

“…All patients gave written informed consent before participation in the trial. Efficacy of fixed-dose capecitabine and preliminary data on the relationships between plasma deoxynucleoside concentrations and TYMS TSER genotype and folate status with capecitabine treatment outcomes have been published elsewhere (26,28).…”