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

Giuseppe Pizzorno, Sandra J. Davis, Dennis Hartigan-O'Connor, Orsola Russello

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1981-1988
Number of pages8
JournalBiochemical Pharmacology
Volume47
Issue number11
DOIs
StatePublished - Jun 1 1994
Externally publishedYes

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Keywords

  • 5-fluorouracil
  • biochemical modulation
  • chemotherapy
  • colon cancer
  • deazafolate
  • murine

ASJC Scopus subject areas

  • Pharmacology

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