Antitumour activity, toxicity and inhibition of thymidylate synthase of prolonged administration of 5-fluorouracil in mice.
Continuous infusions of 5-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, haematological 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 activity 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. Coadministration 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 microM 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.
Codacci-Pisanelli
G
G
Department of Clinical Medicine, University of Rome La Sapienza, Italy.
van der Wilt
C L
CL
Pinedo
H M
HM
Franchi
F
F
Noordhuis
P
P
Braakhuis
B J
BJ
van Laar
J A
JA
Peters
G J
GJ
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D002940:Circadian Rhythm; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D003692:Delayed-Action Preparations; D005472:Fluorouracil / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
D003692:Delayed-Action Preparations; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil