CPT‐11 Alters the Circadian Rhythm of Dihydropyrimidine Dehydrogenase mRNA in Mouse Liver

Combination chemotherapy consisting of 5‐fluorouracil (5‐FU) and 7‐ethyl‐10‐[4‐(l‐piperidino)‐l‐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.