ENHANCEMENT OF ANTINEOPLASTIC ACTIVITY OF 5-FLUOROURACIL IN MICE BEARING COLON-38 TUMOR BY (6R)5,10-DIDEAZATETRAHYDROFOLIC ACID

(6R)5,10-Dideazatetrahydrofolic acid (DDATHF, Lometrexol), a potent an titumor drug in vivo and in vitro, is an inhibitor of the two folate-d ependent enzymes in the de novo purine biosynthesis pathway: glycinami de ribonucleotide (GAR) and amino imidazole carboxamide (AICAR) transf ormylases. A single dose of DDATHF (50 mg/kg, i.p.) in C57/BL6 mice ca used a prolonged depletion of purine nucleotides (ATP and GTP) in colo n 38 tumor and only a temporary effect in liver. GAR transformylase ac tivity was higher in colon 38 tumor than in liver, but a kinetic analy sis on the purified enzyme showed no differences in K-i values for DDA THF or K-m values for the folate substrate. As a consequence of de nov o purine synthesis inhibition, there was a 2- to 3-fold elevation of 5 -phosphoribosyl-1-pyrophosphate pools in colon 38 tumor between 4 and 12 hr after DDATHF administration. When DDATHF (50 mg/kg) was administ ered 4 or 8 hr prior to 5-fluorouracil (5-FU; 85 mg/kg, i.p., weekly), these biochemical effects significantly increased the antitumor activ ity of 5-FU, with a modest increase in toxicity. Lower doses of DDATHF (25 and 37.5 mg/kg) when combined with 5-FU also resulted in an impro ved antitumor activity without additional toxicity. The two different schedules of administration for DDATHF, 4 and 8 hr prior to 5-FU, show ed no differences in antitumor activity or toxicity.