Aspects of one-carbon folate cycling related to fluoropyrimidine and antifolate therapy

Spears, C. P.; Carlsson, Göran; Muggia, Franco M.; Jaresko, George S.; Gustavsson, Bengt

doi:10.1007/978-1-4615-2007-8_6

Cited by 8 publications

(3 citation statements)

References 79 publications

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“…However, LV must be metabolized within the cell through multiple intracellular enzymatic steps to form CH 2 THF [9–12]. In general, CH 2 THF levels are relatively low, in the range of approximately 0.1–0.5 μ mol/L in normal cells, and even lower in human cancer biopsy tissues.…”

Section: Rationalementioning

confidence: 99%

CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

Saif

Makrilia

Syrigos

2010

Journal of Oncology

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Intracellular reduced folate exists as a “pool” of more than 6 interconvertable forms. One of these forms, 5,10 methylenetetrahydrofolic acid (CH2THF), is the key one-carbon donor and reduced folate substrate for thymidylate synthase (TS). This pathway has been an important target for chemotherapy as it provides one of the necessary nucleotide substrates for DNA synthesis. The fluoropyrimidine 5-fluorouracil (5-FU) exerts its main cytotoxic activity through TS inhibition. Leucovorin (5-formyltetrahydrofolate; LV) has been used to increase the intracellular reduced folate pools and enhance TS inhibition. However, it must be metabolized within the cell through multiple intracellular enzymatic steps to form CH2THF. CoFactor (USAN fotrexorin calcium, (dl)-5,10,-methylenepteroyl-monoglutamate calcium salt) is a reduced folate that potentiates 5-FU cytotoxicity. According to early clinical trials, when 5-FU is modulated by CoFactor instead of LV, there is greater anti-tumor activity and less toxicity. This review presents the emerging role of CoFactor in colorectal and nongastrointestinal malignancies.

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Section: Rationalementioning

confidence: 99%

CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

Saif

Makrilia

Syrigos

2010

Journal of Oncology

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“…In order to get a complete inhibition of TS, the active metabolite 5,10-MeTHF must be in excess. Then, a maximal formation of the ternary complex consisting of TS, FdUMP, and 5,10-MeTHF can be achieved [16, 17]. …”

Section: Introductionmentioning

confidence: 99%

Relationship between folate concentration and expression of folate-associated genes in tissue and plasma after intraoperative administration of leucovorin in patients with colorectal cancer

Taflin

Odin

Derwinger

et al. 2018

Cancer Chemother Pharmacol

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PurposeThe aim of study was to investigate the relationship between folate concentration and expression of folate-associated genes in tumour, mucosa and plasma of patients with colorectal cancer, after intraoperative administration of bolus leucovorin (LV).MethodsEighty patients were randomized into four groups to receive 0, 60, 200, or 500 mg/m2 LV, respectively. Tissue and plasma folate concentrations were assessed by LC–MS/MS. Gene expression of ABCC3/MRP3, FPGS, GGH, MTHFD1L, SLC46A1/PCFT, and SLC19A1/RFC-1 was determined using quantitative PCR.ResultsThe folate concentration in tumour increased with increasing dosage of LV. Half of the patients treated with 60 mg/m2 did not reach a level above the levels of untreated patients. A significant correlation between folate concentration in tumour and mucosa was found in untreated patients, and in the group treated with 60 mg/m2 LV. The 5-MTHF/LV ratio correlated negatively with folate concentration in mucosa, whereas a positive correlation was found in tumour of patients who received 200 or 500 mg/m2 LV. A positive correlation was found between folate concentration and expression of all genes, except MTHFD1L, in patients who received LV. There was a negative correlation between 5-MTHF concentration in plasma of untreated patients and expression of GGH and SLC46A1/PCFT in tumour.ConclusionsThe results indicate the possibility of using the individual plasma 5-MTHF/LV ratio after LV injection as a surrogate marker for tissue folate concentration. Expression of several folate-associated genes is associated with folate concentration in tissue and plasma and may become useful when predicting response to LV treatment.Electronic supplementary materialThe online version of this article (10.1007/s00280-018-3690-9) contains supplementary material, which is available to authorized users.

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“…Chemotherapeutic drugs such as 5-fluorouracil (5-FU) affect the de novo synthesis of dTMP by thymidylate synthase (TS) in cancer cells [1,2], The clonal expansion of tumor cells with high TS gene expression levels is one of the major factors responsible for the development of resistance to 5-FU in patients undergoing chemotherapy [1][2][3][4], Currently, the ultrasensitive TS protein binding assay is one of the most effective means of measuring TS gene expression levels in tumor biopsies [5]. Nevertheless many practical limitations exist when measuring protein levels in very small amounts of tissue, a more amenable alternative to directly mea suring TS protein levels in determining tumor sensitivity to 5-FU is to measure TS gene expression [6,7], Northern blot analysis is routinely used to determine gene expression levels in various tissues; however, this method requires microgram quantities of mRNA [8].…”

Section: Introductionmentioning

confidence: 99%

Rapid Detection of Thymidylate Synthase Gene Expression Levels by Semi-Quantitative Competitive Reverse Transcriptase Polymerase Chain Reaction followed by Quantitative Digital Image Analysis

Houze¹,

Larsson²,

Larsson³

et al. 1996

Tumor Biol

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We describe a simplified and reliable polymerase chain reaction (PCR) method to quantify thymidylate synthase (TS) gene expression levels from clinical human tumor biopsy samples as small as 100 mg using the Β-actin housekeeping gene as a reference standard. The semiquantitative RT-PCR is carried out by the coamplification of the target template and an external competitor using primer pairs common to both templates in the same reaction vessel. Quantitative digital image analysis is performed directly after electrophoresis, thus mRNA quantification is done quickly and without the use of radioactive substances. The observed relative TS gene expression levels varied between 3- and 40-fold, but most of the values were grouped within a 10-fold range. There is an observed 89% correlation between TS mRNA expression and protein levels. These findings suggest that preliminary experiments used to determine the linear range of RT-PCR amplification in non-competitive semiquantitative PCR experiments, and the use of radioactive substances to quantify PCR products may be unnecessary.

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Aspects of one-carbon folate cycling related to fluoropyrimidine and antifolate therapy

Cited by 8 publications

References 79 publications

CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

Relationship between folate concentration and expression of folate-associated genes in tissue and plasma after intraoperative administration of leucovorin in patients with colorectal cancer

Rapid Detection of Thymidylate Synthase Gene Expression Levels by Semi-Quantitative Competitive Reverse Transcriptase Polymerase Chain Reaction followed by Quantitative Digital Image Analysis

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