Chronomodulated administration of Capecitabine - Aspects for clinical outcome

Abstract

The activity of the most chemotherapeutic agents is defined by the damage they can cause in healthy host tissues. This renders the establishment of the maximum tolerated dose a key step in anticancer treatment. The majority of anticancer agents, including fluoropyrimidines, exert their cytotoxicity during cell division of tumor or healthy cells. In particular, 5-fluorouracil (5-FU) and capecitabine are more toxic against cells that are in S-phase of the cell cycle. Consequently, cells that undergo DNA synthesis are more sensitive to 5-FU and capecitabine. Hence, 5-FU and capecitabine cytotoxicity depends on the cell cycle phase as well as drug metabolism and elimination. Cell division and drug exposure present circadian variation which is regulated by the circadian timing system (CTS)1. Studies in rodents have shown that several enzymes, which are important for fluoropyrimidine metabolism, show circadian variation. These enzymes include uridine phosphorylase (UP), orotate phosphoribosyl-transferase (OPRT), thymidine kinase (TK), dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) that is the target enzyme of the drug2–4. Clearance of 5-FU is rate-limited by DPD. The circadian rhythm of TS and DPD has been studied in humans. Results have shown that DPD activity peaks and TS activity plunges around the middle of resting span1,5. Therefore, 5-FU and capecitabine are probably best tolerated during rest. In chronomodulated treatment, drugs are administered near their respective times of best tolerability. 5-FU and capecitabine chronotherapy is tested in several clinical trials. In some clinical trials, 5-U chronotherapy showed an improvement in tolerability versus conventional therapy. Chronomodulated treatment with capecitabine was not very advantageous in comparison to conventional treatment, for all patients. Great response variability has been observed according to gender. Men will potentially benefit from chronotherapy more than women. There is evidence that sensitivity to 5-FU and capecitabine depends on different molecular markers6. In addition, several factors like age, gender, different chronotypes and scheduling of chronotherapy can critically affect the outcome of the treatment. Therefore these factors should be taken into consideration in order to achieve more consistent results from clinical studies.