THE EFFECT OF DIFFERENT ROUTES OF ADMINISTRATION OF 5-FLUOROURACIL ONTHYMIDYLATE SYNTHASE INHIBITION IN THE RAT

A rat colon tumour model of liver metastases was used to administer 5- fluorouracil (5FU) by intraperitoneal (i.p.) bolus injection (50 mg/kg ), isolated liver perfusion (ILP, 150 mg/kg) and hepatic artery infusi on (HAI, 50 mg/kg). The biochemical effect of 5FU, delivered by differ ent routes, on its target enzyme thymidylate synthase (TS) was studied in both tumour and normal tissues of the rat. In tumour tissue, only small differences were observed in the extent of TS inhibition. A pron ounced inhibition of TS was observed 3 h after 5FU administration by a ll routes, but was followed by a recovery of TS activity within 24 and 48 h. Effects of 5FU on normal tissues were diverse. In liver, TS act ivity increased 6-fold after ILP and HAI administration of 5FU, and a 2-fold increase of FdUMP binding to TS was seen for all routes of admi nistration. In intestinal mucosa, both induction of TS activity (by IL P) and inhibition of TS activity (by HAI) were observed, while i.p. in jection did not cause major changes. TS activity and FdUMP binding to TS in bone marrow was strongly inhibited after administration of 5FU b y all routes, but administration by ILP seemed slightly advantageous, since a smaller extent of TS inhibition was observed compared to the o ther routes of administration. 5FU given by ILP had a small antitumour effect in this colon tumour model, while HAI administration had no an titumour activity. Since this difference in antitumour activity could not be related to differences in TS inhibition in the tumour, the RNA- directed mechanism of action of 5FU could be involved. Focusing on the effects of TS, we may conclude that the ILP administration of 5FU off ered the important advantage of a lack of severe TS inhibition in norm al tissues, which corresponds with the low systemic toxicity observed.