LAUSR

Simple Summary 5-fluorouracil (5-FU) is the drug used in almost all chemotherapy regimens for colorectal cancer. To potentiate the drug effect, 5-FU is most often combined with the folate leucovorin (LV). Although 5-FU dosage to some extent is individualized, LV dosage is not. To address the issues of LV dosage and administration this randomized pharmacokinetic study was performed comparing different LV dosages as well as infusion and bolus injection administration regimens. Folate concentrations in blood, tumor, mucosa and resection margins were analyzed as was tissue gene expression. In conclusion, different metabolic mechanisms appear to be induced when LV is administered as two-hour infusion or bolus injection, respectively. To achieve maximal inhibition of the 5-FU target enzyme thymidylate synthase (TS), an excess of the polyglutamated folate metabolite methylenetetrahydrofolate (MeTHF) is needed. Regarding polyglutamation, our results points in favor of the bolus regimen. These results could be used to optimize the effect of 5-FU. Abstract The combination of 5-fluorouracil (5-FU) and leucovorin (LV) forms the chemotherapy backbone for patients with colorectal cancer. However, the LV administration is often standardized and not based on robust scientific data. To address these issues, a randomized pharmacokinetics study was performed in patients with colon cancer. Thirty patients were enrolled, receiving 60, 200 or 500 mg/m2 LV as a single two-hour infusion. Blood, tumor, mucosa, and resection margin biopsies were collected. Folate concentrations were analyzed with LC-MS/MS and gene expression with qPCR. Data from a previous study where patients received LV as bolus injections were used as comparison. Saturation of methylenetetrahydrofolate (MeTHF) and tetrahydrofolate (THF) levels was seen after two-hour infusion and polyglutamated MeTHF + THF levels in tumors decreased with increasing LV dosage. The decrease was associated with decreased FPGS and increased GGH expression, which was not observed after LV bolus injection. In the bolus group, results indicate activation of a metabolic switch possibly promoting TYMS inhibition in response to 5-FU. Different metabolic mechanisms appear to be induced when LV is administered as infusion and bolus injection. Since maximal inhibition of TYMS by the 5-FU metabolite 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) requires excess polyglutamated MeTHF, the results point in favor of the bolus regimen.