Circadian rhythm-modulated chemotherapy with high dose 5-fluorouracil against gastrointestinal cancers: evaluation and case report

Nagoya J Med Sci. 1999 May;62(1-2):29-38.


Circadian variations in chemotherapy toxicity and antitumor effects were investigated in experimental and clinical studies. In the experimental study, Balb/c mice bearing murine colon carcinoma Colon 26 were treated with 4 injections of 5-fluorouracil (5-FU) (80 mg/kg) at 0000 Hours After Light On (HALO), 0600 HALO, 1200 HALO and 1800 HALO. The antitumor effect of treatment at 0000 HALO (early resting phase) group was significantly better with lower toxicity than the 1200 HALO (early activity phase) group, resulting in significantly longer survival (p < 0.05). In the clinical study, the effect of circadian rhythm-modulated 5-FU plus leucovorin therapy was evaluated in an end-stage patient with recurrent gastric carcinoma. After continuous weekly infusion of 5-FU (1000 mg/m2/day x 2) was stopped because of its gastrointestinal toxicity, circadian rhythm-modulated chemotherapy (CRMC) was performed changing the dose of 5-FU to 666 mg/m2/day during the daytime (0500 to 1700) and to 1333 mg/m2/day from evening to night (1700 to 0500). The patient persevered with the 23 CRMC course without any signs of severe side effects and survived for nearly a year, suggesting the potential effect of CRMC in minimizing toxicity and prolonging survival.

Publication types

  • Case Reports

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Circadian Rhythm / physiology*
  • Dose-Response Relationship, Drug
  • Evaluation Studies as Topic
  • Fluorouracil / therapeutic use*
  • Gastrointestinal Neoplasms / drug therapy*
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged


  • Antimetabolites, Antineoplastic
  • Fluorouracil