Cancer chronotherapy: Principles, applications, and perspectives

We read with particular interest the article by Drs. Mormont and Levi regarding the clinical implications of chronobiolgy and chronotherapy.1 The circadian cellular organization is responsible for predictable changes in the tolerability and efficacy of anticancer agents. Notably, the administration of a drug at a circadian time when it is best tolerated usually achieves best antitumor activity. This was found to be true for many anticancer drugs, such as 5-fluorouracil (5-FU) and other fluoropyrimidines.2 Thymidylate synthase (TS), one of the key enzymes controlling DNA replication, is a target enzyme for numerous anticancer drugs, among which 5-FU represents the fundamental one. Tumor tissue expression of TS has been shown to be a factor that is predictive of prognosis in primary colorectal carcinoma3 and in metastatic disease.4 Moreover, TS levels also may predict the sensitivity of tumor cells to 5-FU, which is widely used both in the adjuvant setting and in the treatment of disseminated colorectal carcinoma.5, 6 Our research group performed a retrospective study (unpublished data) to investigate the relevance of TS expression (using immunohistochemical staining) in normal colonic tissue as a predictive marker of toxicity in patients with Dukes Stage B and C colorectal carcinoma who were treated with adjuvant 5-FU-based chemotherapy (according to the Mayo Clinic schedule). Our findings suggested that nuclear TS expression in normal colonic mucosa may represent an important predictive parameter with which to identify a subset of patients at high risk of developing severe gastrointestinal toxicities related to 5-FU-based chemotherapy. In particular, the incidence of Grade 2-3 diarrhea and stomatitis (according to the World Health Organization) has been demonstrated to be significantly higher in patients with lower nuclear TS expression in normal mucosa compared with patients with higher TS expression. Therefore, all these results suggest that the evaluation of TS expression in the normal colonic mucosa by immunohistochemical staining may represent an easy and low-cost method with which to identify patients at high risk of developing 5-FU-induced gastrointestinal toxicities. Moreover, using a murine model, Lincoln et al. demonstrated that TS expression in normal tissues follows a circadian rhythm and that this circadian organization of TS most likely contributes in vivo to the time of day differences in the toxic-therapeutic ratio of circadian-timed fluoropyrimidine drug therapy.7 Furthermore, Bjarnason et al. demonstrated that the circadian clock may, in part, control the timing of cell cycle events (TS activity) in human tissues undergoing continuous circadian rhythms in proliferation (gastrointestinal mucosa, skin, and bone marrow).8 In conclusion, a circadian rhythm for fluoropyrimidine drug-related toxicities and toxicity predicting role of TS expression in normal colonic mucosa has been suggested on the basis of our findings. As a consequence, the circadian rhythm of TS in normal gastrointestinal mucosa may play a key role in the development of side effects in patients receiving anticancer chronotherapy and may be considered to be a major determinant of 5-FU chronopharmacology. Future trials should be performed to evaluate the clinical impact of nuclear TS staining in normal gastrointestinal mucosa to predict the risk of toxicities in colorectal carcinoma patients treated with 5-FU-based chronotherapy.