BACKGROUND: 5-Fluorouracil (5-FU) is a cornerstone in treatment of colorectal cancer (CRC) and is usually combined with leucovorin (LV) to enhance the antitumour effect by increase thymidylate synthase (TS) inhibition, the key target enzyme for 5-FU. Arfolitixorin (Arfo) is an active form of the reduced folate, [6 R]-5,10-methylenetetrahydrofolate ([6 R]-MeTHF and in contrast to LV, does not need to be metabolized. The Modelle-001 was designed to explore whether a single intravenous bolus injection of Arfo as compared to LV, together with 5-FU increases the inhibition of TS, levels of folate concentrations and polyglutamylation in CRC liver metastases (CRLM) and liver parenchyma.

PATIENTS AND METHODS: Thirty patients with CRLM received either LV (60 mg/m²) or Arfo (30 mg/m² or 120 mg/m²) in combination with 5-FU preoperatively. Levels of folates and and TS inhibition were measured.

RESULTS: Significantly higher MeTHF levels and higher TS inhibition were measured in the Arfo groups compared to LV60, and there was a difference in folate poly-glutamylation between the groups.

CONCLUSION: The Modelle-001 Trial demonstrated significantly higher levels of MeTHF in metastases following Arfo compared to LV. This resulted in a greater increase TS inhibition in metastases although not statistically significant.