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 antitumor drug in vivo and in vitro, is an inhibitor of the two folate-dependent enzymes in the de novo purine biosynthesis pathway: glycinamide ribonucleotide (GAR) and amino imidazole carboxamide (AICAR) transformylases. A single dose of DDATHF (50 mg/kg, i.p.) in C57/BL6 mice caused a prolonged depletion of purine nucleotides (ATP and GTP) in colon 38 tumor and only a temporary effect in liver. GAR transformylase activity was higher in colon 38 tumor than in liver, but a kinetic analysis on the purified enzyme showed no differences in Ki values for DDATHF or Km values for the folate substrate. As a consequence of de novo 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 administered 4 or 8 hr prior to 5-fluorouracil (5-FU; 85 mg/kg, i.p., weekly), these biochemical effects significantly increased the antitumor activity 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 improved antitumor activity without additional toxicity. The two different schedules of administration for DDATHF, 4 and 8 hr prior to 5-FU, showed no differences in antitumor activity or toxicity.
Pizzorno
G
G
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
Davis
S J
SJ
Hartigan
D J
DJ
Russello
O
O
D000217:Acyltransferases / Q000032:analysis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D019877:Hydroxymethyl and Formyl Transferases; D051379:Mice; D008810:Mice, Inbred C57BL; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase; D011685:Purine Nucleotides / Q000096:biosynthesis; D013763:Tetrahydrofolates / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011685:Purine Nucleotides; D013763:Tetrahydrofolates; C045894:lometrexol; D010754:Phosphoribosyl Pyrophosphate; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase; D000217:Acyltransferases; D005472:Fluorouracil