Disease relevance of folinic acid

• Therapeutic approaches with either pyridoxine (50 mg d-1) alone or in combination with N5-formyltetrahydrofolate (3 X 3 mg d-1) or with strychnine (0.3 mg per kg body weight) did not result in improvement [1].

High impact information on folinic acid

• The rescue of lymphocytes from methotrexate (MTX) growth inhibition by 5-methyltetrahydrofolate (5-methyl-THF) and 5-formyltetrahydrofolate (5-formyl-THF) has been studied [2].
• At MTX concentrations which inhibited growth greater than or equal to 85% in both leukemic T-lymphocytes (CCRF-CEM) and Epstein-Barr-transformed B-lymphocytes (LAZ-007), 5 micro M 5-formyl-THF rescued more effectively than did 5-methyl-THF, in either the presence or absence of the methyltransferase inhibitor, nitrous oxide [2].
• In yeast lacking MTHFS along with both AICAR transformylases, 5-CHO-THF was elevated 12-fold over wild type [3].
• 5-CHO-THF was undetectable in strains lacking SHMT activity, confirming SHMT as the in vivo source of 5-CHO-THF [3].
• Growth phenotypes of multiply disrupted strains are consistent with a regulatory role for 5-CHO-THF in one-carbon metabolism and additionally suggest a metabolic interaction between the purine and methionine pathways [3].

Biological context of folinic acid

• The functional expression of the mutated RFC1 reduced the growth requirement for 5-CHO-THF by a factor of 30, compared with only a 3-fold decrease in the MTX IC50 [4].
• The ability of formyl-H4F to enhance the binding of QscR to a specific region upstream of one of the serine cycle operons was demonstrated in gel retardation experiments [5].
• The VPA plasma kinetics were not changed by any of the application regimens of 5-CHO-THF [6].
• Oral dose proportionality and pharmacokinetics of leucovorin [(d,l)-5-formyltetrahydrofolate (5-formyl-THF)] were studied in 30 healthy male subjects [7].

Anatomical context of folinic acid

• This cell line was 10-fold resistant to MTX in comparison to parental L1210 cells, yet the EC50 for 5-CHO-THF was increased by a factor of only 2 [4].
• N5-Formyltetrahydrofolate, a competitive inhibitor of the formylation of the initiator Met-tRNAfMet in an in vitro assay, is a powerful inhibitor of amino acid incorporation in isolated Saccharomyces cerevisiae mitochondria and in Euglena gracilis chloroplasts [8].

Associations of folinic acid with other chemical compounds

• In an ongoing study of structure-function relationships of the murine reduced folate carrier 1 (RFC1), a glutamate to lysine mutation at amino acid 45 was identified in a methotrexate (MTX)-resistant L1210 clonal variant in which MTX and 5-formyltetrahydrofolate (5-CHO-THF) influx was markedly decreased [9].
• This study represents another example of a single mutation in RFC1 that markedly impairs MTX influx but partially preserves transport of reduced folates when cells are selected with 5-CHO-THF as the available folate substrate [10].
• Folinic acid (5-CHO-THF) coadministration by i.p. injection or by a constant rate infusion via osmotic minipumps, implanted s.c., significantly reduced the exencephaly rates using a randomized double-blind experimental procedure [6].
• The affinity of both rat proteins is highest for pteroylglutamic acid (Ka = 1.6.10(9) l/mol) lower for N5-methyltetrahydrofolate and substantially lower for N5-formyltetrahydrofolate [11].

Gene context of folinic acid

• A variant line (CEM-7A) "overproducing" the reduced folate/MTX carrier system was isolated from human CCRF-CEM leukemia cells grown under selective conditions in medium containing 0.25 nM 5-formyl-THF as the sole folate source [12].
• 5-CHO-THF supplementation cut the exencephaly rates into half even at high maternal plasma levels of VPA (p less than 0.005, chi 2-test); resorption rates were not affected [6].

Analytical, diagnostic and therapeutic context of folinic acid

• The investigation of the folate metabolite pattern (determined by HPLC) showed that 5-CHO-THF and 5-methyl-tetrahydrofolic acid (5-CH3-THF) were the main metabolites in untreated mice [6].
• In a randomized cross-over design, 24 fasted subjects were given 4 of a series of 5 single test doses between 20 and 100 mg, at 1-week intervals, of 5-formyl-THF as an oral solution of leucovorin calcium [7].

References