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-(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.
Shimizu
M
M
Pharmacology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Tamura
T
T
Yamada
Y
Y
Akiyama
Y
Y
Saijo
N
N
Nishio
K
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology; D002940:Circadian Rhythm; D003600:Cytosol / Q000201:enzymology; D042943:Dihydrouracil Dehydrogenase (NADP); D004305:Dose-Response Relationship, Drug; D005472:Fluorouracil / Q000008:administration & dosage; D007150:Immunohistochemistry; D000077146:Irinotecan; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*
D012333:RNA, Messenger; D000077146:Irinotecan; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; D002166:Camptothecin