ANTITUMOR-ACTIVITY, TOXICITY AND INHIBITION OF THYMIDYLATE SYNTHASE OF PROLONGED ADMINISTRATION OF 5-FLUOROURACIL IN MICE

Continuous infusions of 5-fluorouracil (5-FU) ate 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 implant ed pellets that release 5-FU over a period of 3 weeks. At the maximum tolerated dose (MTD) (based on the systemic toxicity in healthy animal s) we assessed the antitumour activity, haematological toxicity, inhib ition 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 m ouse myelosuppression was tolerable (nadir for leucocytes and thromboc ytes was approximately 40% of pretreatment levels). In several indepen dent experiments using the 5-FU-resistant Colon 26 tumour, a good anti tumour activity was observed during the first part of the infusion, bu t 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 result s; depending on the schedule used, it proved ineffective or only incre ased toxicity. Similar results were obtained with head and neck squamo us cell carcinomas and with the 5-FU-sensitive tumour Colon 38. In Col on 26 tumours the TS activity (FdUMP-binding assay) initially decrease d to 20-30% of controls and returned to normal after 11 days. In the c atalytic TS assay a slight inhibition was observed for the continuous infusion, followed after 11 days by a marked (4-fold) increase in acti vity. 5-FU plasma levels varied from 0.1 to 1 mu M following a circadi an 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 befo re transferring data obtained in vitro to the clinic.