Increased potentiation of 5-fluorouracil induced thymidylate synthase inhibition by 5,10-methylenetetrahydrofolate (arfolitixorin) compared to leucovorin in patients with colorectal liver metastases; The Modelle-001 Trial
Helena Taflin,
Elisabeth Odin,
Göran Carlsson,
Bengt Gustavsson,
Oskar Hemmingsson,
Yvonne Wettergren,
Krzysztof Urbanowicz,
Jacek Turyn,
Ryszard T. Smolenski,
Godefridus J. Peters
Affiliations
Helena Taflin
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
Elisabeth Odin
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
Göran Carlsson
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
Bengt Gustavsson
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
Oskar Hemmingsson
Department of Diagnostics and Intervention/Surgery, Umeå University
Yvonne Wettergren
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg
Krzysztof Urbanowicz
Department of Biochemistry, Medical University of Gdansk
Jacek Turyn
Department of Biochemistry, Medical University of Gdansk
Ryszard T. Smolenski
Department of Biochemistry, Medical University of Gdansk
Godefridus J. Peters
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (Amsterdam UMC), Vrije Universiteit Amsterdam
Abstract 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.
