Tissue Levels of Reduced Folates in Patients with Colorectal Carcinoma After Infusion of Folinic Acid at Various Dose Levels

Wettergren

et al. 2014

PurposeCalcium folinate (leucovorin), which is converted in vivo into biologically active folate, enhances the potency of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer. A common dosage of leucovorin in adjuvant and palliative settings is 60 mg/m2. The aim was to determine the levels of tetrahydrofolate (THF), 5,10-methylenetetrahydrofolate (methyleneTHF), and 5-methyltetrahydrofolate (methylTHF) in tumour and mucosa of colorectal cancer patients who received different dosages of leucovorin intravenously at time of surgery.MethodsEighty patients scheduled for colorectal resection with indication of colorectal cancer were randomised into four groups to receive leucovorin at 0, 60, 200, or 500 mg/m2, respectively. Blood samples were taken 10 and 30 min after leucovorin administration. Biopsy samples from tumour and mucosa were collected and snap-frozen at surgery. The levels of THF, methyleneTHF, and methylTHF in tumour and mucosa were assessed by liquid chromatography electrospray ionisation tandem mass spectrometry (LC–MS/MS) and the results were related to clinical diagnosis and therapeutic regimens.ResultsThe folate levels in tissue revealed extensive inter-individual variability. The mean methyleneTHF value for the four treatment groups were 880, 1,769, 3,024 and 3,723 pmol/gww. Only half of the patients who received 60 mg/m2 leucovorin had higher levels of methyleneTHF in tumour than patients who received 0 mg/m2 leucovorin. Rectal cancer patients had significantly lower levels of methyleneTHF compared with colon cancer patients.ConclusionsThere was a large inter-patient variability of tissue folate levels in colorectal cancer patients after supplementation with leucovorin at standardised dosage. High leucovorin doses were needed to exceed baseline methyleneTHF values, especially in rectal cancer patients. The results indicate that the standardised leucovorin dose may be insufficient to attain the full antitumour effect of 5-FU. Further studies are needed to establish whether higher dosage yields a better treatment response.

Section: Discussionsupporting

confidence: 88%

Folate levels measured by LC–MS/MS in patients with colorectal cancer treated with different leucovorin dosages

Wettergren

et al. 2014

“…The results of the present study showed that there was a high inter-individual variation of folates in both tumour and mucosa. This finding is in agreement with previous results published by our group [ 18 ] as well as by others [ 23 ]. Higher concentrations were found in tumour tissue compared to mucosa in all patient groups.…”

Section: Discussionsupporting

confidence: 94%

“…This finding is in agreement with previous results published by our group [18] as well as by others [23]. Higher concentrations were found in tumour tissue compared to mucosa in all patient groups.…”

Section: Discussionsupporting

confidence: 94%

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

Derwinger

et al. 2018

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.

“…Administration of Modufolin ® instead of LV might circumvent such metabolic obstacles. Furthermore, an abundance of methyleneTHF in the tumor tissue may be generated by using Modufolin ® , which might lead to an increased response to 5-FU-based chemotherapy by stabilization of the ternary complex [ 11 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

A pharmacokinetic and pharmacodynamic investigation of Modufolin® compared to Isovorin® after single dose intravenous administration to patients with colon cancer: a randomized study

Wettergren

et al. 2014

Purpose Leucovorin is commonly used as folate supplement in 5-fluorouracil-based chemotherapy, but needs to be converted to active 5,10-methylenetetrahydrofolate (methyleneTHF) intracellularly. This provides for interindividual differences. MethyleneTHF has recently been developed into the stable, distributable drug, Modufolin®. The aim was to compare the concentration of folate metabolites in tumor, mucosa, and plasma of patients with colon cancer after administration of Modufolin® or Isovorin® (levo-leucovorin).MethodsThirty-two patients scheduled for colon resection were randomized to receive Modufolin® or Isovorin® at dosage of 60 or 200 mg/m2. The study drug was given as one i.v. bolus injection after anesthesia. Plasma was collected for pharmacokinetic (PK) analysis before, during, and after surgery. Tissue biopsies were collected at surgery. Folate metabolites were analyzed by LC-MS/MS.ResultsMethyleneTHF and THF concentrations were significantly higher in mucosa (p < 0.01, both dosages) and tumors (p < 0.01, 200 mg/m2) after Modufolin® as compared to Isovorin® administration. The results correlated with PK observations. The Modufolin® to Isovorin®Cmax ratio for methyleneTHF was 113 at 200 mg/m2 and 52 at 60 mg/m2; the AUClast ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin® administration (Cmax ratio 23, AUClast ratio 13 at 200 mg/m2; Cmax ratio 15, AUClast ratio 11 at 60 mg/m2).ConclusionModufolin® administration resulted in significantly higher methyleneTHF levels than Isovorin® and may potentially increase the efficacy of 5-fluorouracil-based chemotherapy. The results encourage further evaluation of Modufolin® as a substitute to Isovorin® including the potential clinical benefits.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2611-9) contains supplementary material, which is available to authorized users.