Disease relevance of folinic acid

• Finally, the degree of toxicity did not appear to depend on the dose of (6S)-folinic acid over the range of doses tested [1].
• Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer [2].
• Protein-bound folates were also detected in HT29 human colon adenocarcinoma cells grown in 5-formyltetrahydrofolate (maximum, 11 pmol/mg protein) [3].
• 5,10-Methenyltetrahydrofolate synthetase (EC 6.3.3.2), which catalyzes the ATP- and Mg2+ -dependent isomerization of 5-formyl- to 5,10-methenyltetrahydrofolate, has been purified 10,000-fold from Lactobacillus casei using sequential affinity chromatography on immobilized 5-formyltetrahydrofolate and ATP [4].
• Both rabbit liver mitochondrial and Escherichia coli serine hydroxymethyltransferase catalyze the conversion of 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate at rates similar to those observed for the cytosolic enzyme [5].

High impact information on folinic acid

• We also determined the plasma pharmacokinetics of folates after intravenous (IV) injection of (6S)-folinic acid at the dose used in this study [6].
• They may have implications for the identification of patients resistant to FU chemotherapy and for a better understanding and management of FU modulation by folinic acid (FA) [7].
• We investigated the biological activities of the natural and unnatural diastereoisomers of 5-formyltetrahydrofolate [(6S)- and (6R)-5-HCO-H4PteGlu, respectively, both 99.99% pure], using a human ileocecal carcinoma cell line (HCT-8) [8].
• [6RS]Leucovorin (5-formyltetrahydrofolate; 5-CHO-H4PteGlu) administered in different regimens in combination with 5-fluorouracil (FUra) has increased the response rates to FUra in patients with colon adenocarcinoma [9].
• We used our model of HD-MTX neurotoxicity in the rat to determine if leucovorin (5-formyltetrahydrofolate) reduces this neurotoxicity, and extended our characterization of this model to identify regional as well as global HD-MTX treatment effects and to investigate HD-MTX-induced alterations in regional brain pH [10].

Chemical compound and disease context of folinic acid

• Finally, in MCF-7 breast cancer cells there was greater protection with thymidine alone than in HeLa cells when cells were grown in medium containing a low concentration of 5-formyltetrahydrofolate [11].
• Rapid communication: L-folinic acid versus folic acid for the treatment of hyperhomocysteinemia in hemodialysis patients [12].
• In patients with stage III colorectal cancer (CRC) who have undergone potentially curative resection, adjuvant treatment with 6 months' of 5-fluorouracil (5-FU) plus folinic acid (FA) is generally accepted as standard treatment and leads to a 5% to 10% improvement in absolute survival when compared with a no-chemotherapy control [13].
• A recent controlled trial suggests that overall time to progression is maximized and toxicity minimized when an irinotecan/5-FU/FA combination is used first-line, followed by an oxaliplatin/ 5-FU/FA combination on progression [14].
• In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients [15].

Biological context of folinic acid

• Mechanism for the coupling of ATP hydrolysis to the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate [16].
• Cell growth inhibition by these compounds was prevented by 5-formyltetrahydrofolate in a dose-dependent manner [17].
• The results also showed that only one rotamer of 5-formyltetrahydrofolate binds at the active site of serine hydroxymethyltransferase [18].
• Serine hydroxymethyltransferase, in the presence of glycine, catalyzes the conversion of chemically synthesized 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate with biphasic kinetics [5].
• This down-regulation during incubations with 5-formyltetrahydrofolate or 5-methyltetrahydrofolate could be prevented by either the addition of 10-25 nM of the lipophilic antifolate trimetrexate or by preincubating CEM-7A cells with 25 nM methotrexate [19].

Anatomical context of folinic acid

• Both (6S)- (unnatural) and (6R)-10-HCO-THF supported the respiration of mitochondria, whereas (6S)-5-formyltetrahydrofolate (5-HCO-THF) was inactive [20].
• It is hypothesized that mildly acidic subcellular organelles provide an environment for the hydrolysis of 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate in vivo, and there is no requirement for enzyme catalysis [21].
• Uptake of 5-formyltetrahydrofolate in isolated rat liver mitochondria is carrier-mediated [22].
• FA determined a significant increase in CFU-GM on the 5th day of administration, as well as in BFU-E on day 7 [23].
• Transport of 5-formyltetrahydrofolate into primary cultured rat astrocytes [24].

Associations of folinic acid with other chemical compounds

• Methotrexate rescue by 5-methyltetrahydrofolate or 5-formyltetrahydrofolate in lymphoblast cell lines [25].
• Folate cofactors are highly susceptible to oxidative degradation in vitro with the exception of 5-formyltetrahydrofolate, which may be a storage form of folate [26].
• Polyclonal antibodies against recombinant dehydrogenase reacted with protein methylase I purified either by polyacrylamide gel electrophoresis or 5-formyltetrahydrofolate affinity chromatography [27].
• EXPERIMENTAL DESIGN: We have replaced 5-FU in the weekly combination of CPT-11, folinic acid (FA) and 5-FU chemotherapy by 5-FC and an adenoviral vector that carries the L-plastin (Lp) tumor-specific promoter-driven transcription unit encoding the cytosine deaminase gene linked to the E1A gene by an internal ribosomal entry site element [28].
• When grown with folic acid (2 micro M) at pH 7.4, the IC(50) for MTX was 14-fold higher in R5 as compared with wild-type HeLa cells; the difference was only 4-fold when cells when grown at pH 6.9; the IC(50)s were identical at this pH when the medium folate was 25 nM 5-formyltetrahydrofolate [29].

Gene context of folinic acid

• Using an oligonucleotide probe complementary to the human FBP, we have cloned and sequenced two murine FBP cDNAs isolated from a library constructed using a L1210 subline adapted for growth on low levels of 5-formyltetrahydrofolate [30].
• Methenyltetrahydrofolate synthetase (MTHFS) catalyses the obligatory initial metabolic step in the intracellular conversion of 5-formyltetrahydrofolate to other reduced folates [31].
• However, whether in the absence or presence of FA, FU sensitivity was not statistically associated with either 5' or 3' TS polymorphism [32].
• When grown with 25 nmol/L racemic 5-formyltetrahydrofolate, thymidine alone fully protected wild-type HeLa cells to at least 1 micromol/L pemetrexed, but protection of a reduced folate carrier (RFC)-null subline required both thymidine and hypoxanthine above a concentration of 30 nmol/L pemetrexed [11].
• 5-Formyltetrahydrofolate cycloligase (5-FCL) catalyzes the conversion of 5-formyltetrahydrofolate (5-CHO-H(4)PteGlu(n)) to 5,10-methenyltetrahydrofolate and is considered to be the main means whereby 5-CHO-H(4)PteGlu(n) is metabolized in mammals, yeast, and bacteria [33].

Analytical, diagnostic and therapeutic context of folinic acid

• HD-MTX (8 g/m2) therapy with 5-formyltetrahydrofolate "rescue" (stage III) was usually begun about seven weeks after start of chemotherapy, and the patients were followed for two to eight courses separated by three to eight weeks [34].
• CONCLUSIONS: Relative to high-dose FA, high-dose oral L-folinic acid-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients [12].
• We present a rapid, sensitive, and automated HPLC method with direct resolution of l-folinic acid (l-FA), d-folinic acid (d-FA), and 5-methyltetrahydrofolate (5MTHF) from plasma samples [35].
• The thermodynamic parameters for the binding of 5-formyltetrahydrofolate (5-CHO-H4PteGlun) and its polyglutamate forms to rabbit liver cytosolic serine hydroxymethyltransferase (SHMT) were determined by a combination of isothermal titration calorimetry and spectrophotometry [36].
• Adjuvant chemotherapy (5-FU + l-folinic acid) was delivered to 26 patients in the FUMIR-T4 protocol group [37].

References