Antitumour activity, toxicity and inhibition of thymidylate synthase of prolonged administration of 5-fluorouracil in mice

G. Codacci-Pisanelli, C. L. van der Wilt, H. M. Pinedo, F. Franchi, P. Noordhuis, B. J M Braakhuis, J. A M van Laar, G. J. Peters

Research output: Contribution to journalArticle

Abstract

Continuous infusions of 3-fluorouracil (5-FU) are increasingly used in the treatment of cancer. Their optimal use, however, has still to be: determined since the availability of suitable animal models is limited. We studied continuous infusions in mice using subcutaneously implanted pellets that release 5-FU over a period of 3 weeks. At the maximum tolerated dose (MTD) (based on the systemic toxicity in healthy animals) we assessed the antitumour activity, hacmatological toxicity, inhibition of thymidylate synthase (TS) in tumours and the concentration of 5-FU in plasma during the 3-week period. We also studied the addition of leucovorin in different schedules. The dose-limiting toxicity was weight loss, and at the MTD of 10 mg of 5-FU released in 21 days per mouse myelosuppression was tolerable (nadir for leucocytes and thrombocytes was approximately 40% of pretreatment levels). In several independent experiments using the 5-FU-resistant Colon 26 tumour, a good antitumour acitivity was observed during the first part of the infusion, but thereafter the growth of the tumours resumed; the overall effect of continuous infusions was thus comparable to that of bolus injections. Co-administration of leucovorin did not enhance the therapeutic results; depending on the schedule used, it proved ineffective or only increased toxicity. Similar results were obtained with head and neck squamous cell carcinomas and with the 5-FU-sensitive tumour Colon 38. In Colon 26 tumours the TS activity (FdUMP-binding assay) initially decreased to 20-30% of controls and returned to normal after 11 days. In the catalytic TS assay a slight inhibition was observed for the continuous infusion, followed after 11 days by a marked (4-fold) increase in activity. 5-FU plasma levels varied from 0.1 to 1 μM following a circadian rhythm (with a peak at 6 h after light onset), and were maintained during the entire period. Subcutaneously implanted pellets represent a suitable model to study prolonged administration of 5-FU in mice and to evaluate the effect of modulating agents in laboratory animals before; transferring data obtained in vitro to the clinic.

Original languageEnglish (US)
Pages (from-to)1517-1525
Number of pages9
JournalEuropean Journal of Cancer
Volume31
Issue number9
DOIs
Publication statusPublished - 1995
Externally publishedYes

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Keywords

  • 5-fluorouracil
  • continuous infusion
  • thymidylate synthase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Hematology

Cite this

Codacci-Pisanelli, G., van der Wilt, C. L., Pinedo, H. M., Franchi, F., Noordhuis, P., Braakhuis, B. J. M., ... Peters, G. J. (1995). Antitumour activity, toxicity and inhibition of thymidylate synthase of prolonged administration of 5-fluorouracil in mice. European Journal of Cancer, 31(9), 1517-1525. https://doi.org/10.1016/0959-8049(95)00218-8