Combination chemotherapy consisting of 5-fluorouracil (5-FU) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carboxycamptothecin (CPT-11) is a promising regimen for gastrointestinal cancer. The circadian-dependent efficacy and toxicity of 5-FU are related to the circadian variation in the activity of dihydropyrimidine dehydrogenase (DPD), which is a rate-limiting enzyme in the pyrimidine catabolic pathway. To optimize the schedule of the CPT-11 plus 5-FU combination, we investigated the effect of CPT-11 on the circadian rhythm of DPD in vivo. In control mice, the DPD mRNA level in the liver was significantly higher at 14:00 than that at 02:00. After intravenous administration of CPT-11 (30 mg/kg) at 20:00, the circadian rhythm of the DPD mRNA level in the liver was no longer observed 18 h later (14:00), but it was unaffected 6 and 18 h later (at 14:00 and 02:00) when CPT-11 was given at 08:00. In addition, a dose-dependent lengthening of the period of the circadian rhythm of DPD was observed for 42 h after intravenous injection of CPT-11 at 20:00. The levels of DPD protein and activity at 21 h after administration of CPT-11 (at 17:00) were significantly higher than at 9 h (at 05:00). These results suggest that CPT-11 may influence the circadian rhythm of DPD at the transcriptional level. Modulation of the circadian rhythm of DPD by CPT-11 may be a factor in optimizing the combination of 5-FU and CPT-11.Key words: CPT-11 -Dihydropyrimidine dehydrogenase -Circadian rhythm 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carboxycamptothecin (CPT-11) is one of the most potent therapeutic agents for the treatment of solid tumors, including lung, colorectal, and cervical cancer, and malignant lymphoma, 1,2) and combination regimens of CPT-11 and 5-fluorouracil (5-FU) have recently been evaluated in metastatic colorectal cancer patients.3, 4) Combination chemotherapy consisting of CPT-11, 5-FU, and leucovorin has been reported to be well tolerated and to have greater efficacy than 5-FU alone for first-line metastatic colorectal cancer.
5)Dihydropyrimidine dehydrogenase (DPD) is the ratelimiting enzyme in 5-FU catabolism, and it has been found to exhibit circadian variation in experimental animals 6,7) and cancer patients. 8) A study in cancer patients treated with 5-FU showed an inverse relationship between DPD activity in peripheral blood mononuclear cells and the plasma concentration of 8) and the circadian variation in 5-FU toxicity in rats has been reported to be inversely correlated with the circadian variation in DPD activity.
9)The relevance of chronotherapy using 5-FU, folinic acid, and oxaliplatin was investigated in phase II trials in metastatic colorectal cancer patients.
10)The mechanisms regulating circadian rhythms in a variety of species have recently been clarified. In mammals, the suprachiasmatic nucleus (SCN) of the anterior hypothalamus has been shown to be a circadian pacemaker, 11) and the human and mouse homologues of the mammalian period gene, which plays a central role in circadian rhythms, have been iso...