Enhancement of antineoplastic activity of 5-fluorouracil in mice bearing colon 38 tumor by (6R)5,10-dideazatetrahydrofolic acid

Biochem Pharmacol. 1994 Jun 1;47(11):1981-8. doi: 10.1016/0006-2952(94)90072-8.

Abstract

(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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acyltransferases / analysis
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Colonic Neoplasms / drug therapy*
  • Drug Synergism
  • Female
  • Fluorouracil / therapeutic use*
  • Hydroxymethyl and Formyl Transferases*
  • Mice
  • Mice, Inbred C57BL
  • Phosphoribosyl Pyrophosphate / metabolism
  • Phosphoribosylglycinamide Formyltransferase
  • Purine Nucleotides / biosynthesis
  • Tetrahydrofolates / pharmacokinetics
  • Tetrahydrofolates / pharmacology*

Substances

  • Antineoplastic Agents
  • Purine Nucleotides
  • Tetrahydrofolates
  • lometrexol
  • Phosphoribosyl Pyrophosphate
  • Hydroxymethyl and Formyl Transferases
  • Phosphoribosylglycinamide Formyltransferase
  • Acyltransferases
  • Fluorouracil