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The biochemical modulation (BCM) of the antitumor effect of 5-fluorouracil (5-FU) by leucovorin (LV) was studied with xenografts (MC-1, MC-3, MPC-2) by transplanting human tumors to nude mice and by human tumor clonogenic assay (HTCA). For human tumor transplantation to nude mice, the dose of 5-FU was set at LD50 x 0.6 or LD50 x 0.8 and LV was given in three doses, 0.45, 0.15, 0.06 mg/body. Antitumor effects of combined administration of 5-FU and LV at the same time, as compared with that of administration of LV one hour before 5-FU, were examined. The relationship between the rate of inhibition of thymidylate synthetase (T.S) activity and 5-FU concentration in the neoplastic tissues was also examined. In HTCA the antitumor effects of 5-FU were examined by two methods: 1) limited contact for one four, and 2) continuous contact for two weeks. In the human tumor transplantation to nude mice, the BCM of the antitumor effect of 5-FU by LV was demonstrated in MC-1 and MPC-2. This BCM function of LV was enhanced by administering it one hour before 5-FU. The suitable LV dose was between 0.15 and 0.45 mg/body. Although there was a tendency for the rate of inhibition of T.S to be proportional to the tissue concentration of 5-FU, there was no significant relationship between the T.S inhibition rate and the antitumor effect. In HTCA, the BCM function of LV was suggested by the two-week-continuous contact method with MC-1 and MPC-2. Depending on the method of administering LV, the antitumor activity was higher with two-week continuous contact than with one-hour contact. In conclusion, the BCM effect of LV on the antitumor effect of 5-FU was revealed in MC-1 and MPC-2 strains. Further studies are needed to establish a standard for appropriate dosage and administration of LV.

BIOCHEMICAL MODULATION APPLIED TO EXPERIMENTAL CANCER CHEMOTHERAPY