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.
Highlights
Colorectal cancer (CRC) is a major cause of cancer death worldwide [1, 2]
Half of the patients who received 60 mg/m2 LV did not reach a folate concentration in tumour tissue above the level of untreated patients
A large part of patients with CRC may benefit from higher LV doses than recommended, or treatment with folate forms with different metabolic profiles
Summary
The fundament in the treatment of CRC is surgery. After primary surgery, treatment with chemotherapy is recommended for advanced tumour stages [5]. The drug 5-fluorouracil (5-FU) is used as a cornerstone of chemotherapy treatment, in the adjuvant, as well as in the palliative setting for CRC [6,7,8]. This drug is an analogue of uracil, in which the hydrogen at position 5 is replaced by fluorine. 5-FU enters the cell in the same way as uracil and is converted in several steps intracellularly This drug is an analogue of uracil, in which the hydrogen at position 5 is replaced by fluorine. 5-FU enters the cell in the same way as uracil and is converted in several steps intracellularly
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