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

Abstract

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.

Folate receptors and transporters: biological role and diagnostic/therapeutic targets in cancer and other diseases

“…Wettergren in “The use of folate transporters as biomarkers in colorectal cancer therapy ” reported high expression of SLC46A1/PCFT, SLC19A1/RFC-1, and ABCC3/MRP3 was associated with longer 5-year disease-free survival (DFS) of patients with colorectal cancer ( n = 363) treated with adjuvant 5-fluorouracil plus leucovorin (FLV), whereas there was no association between expression and DFS in untreated patients [ 53 ]. Furthermore, a positive association between 3-year progression-free survival and ABCC3/MRP3 expression was found in patients with advanced colorectal cancer ( n = 294).…”

Evaluation of intracellular distribution of folate functionalized silica nanoparticles using fluorescence and hyperspectral enhanced dark field microscopy

“…19 Cancer cells have increased demands of metabolic precursors; 20 thus, the possibility of targeting cancer cells by “feeding” them with DDSs loaded with specific precursors, represents a strategy for an effective perturbation of their evolution. 21–26…”

“…19 Cancer cells have increased demands of metabolic precursors; 20 thus, the possibility of targeting cancer cells by "feeding" them with DDSs loaded with specific precursors, represents a strategy for an effective perturbation of their evolution. [21][22][23][24][25][26] Since folate receptors are highly expressed in various human carcinomas such as: colorectal, heart, lung, kidney, ovarian, breast etc., 7 conjugating nanoparticles (NPs) with folic acid (e.g., gold NPs for cell imaging of nasopharyngeal malignancy 27 ) has proven to be a successful approach for targeting cancer cells for either visualization or drug delivery. [28][29][30][31][32][33][34] The expression level of folate receptors on the cell membrane is influenced by the cellular metabolism, the higher the proliferation rate (as it is naturally occurring in cancer cells), the more receptors are expressed compared to non-malign cells.…”

Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin

“…Previous studies have shown that there is a large interindividual difference in concentration of leucovorin in colorectal tumor tissue in response to a standardized dose of leucovorin [9]. This difference might be related to different expression levels of genes encoding influx and efflux folate transporters and of those involved in conversion of leucovorin to the active metabolite [6R]-MTHF [10][11][12]. Genderand age-associated pharmacokinetic differences have also been reported for folates and most oncologic drugs [13][14][15].…”