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The role of l-leucovorin uptake and metabolism in the modulation of 5-fluorouracil efficacy and antifolate toxicity.
Peters, Godefridus J; Kathmann, Ietje; Giovannetti, Elisa; Smid, Kees; Assaraf, Yehuda G; Jansen, Gerrit.
Afiliación
  • Peters GJ; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Kathmann I; Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland.
  • Giovannetti E; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Smid K; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
  • Assaraf YG; Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy.
  • Jansen G; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Front Pharmacol ; 15: 1450418, 2024.
Article en En | MEDLINE | ID: mdl-39234107
ABSTRACT

Background:

L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a racemic mixture of its l-LV and d-LV stereoisomers. We compared dl-LV with l-LV and investigated whether d-LV would interfere with the activity of l-LV.

Methods:

Using radioactive substrates, we characterized the transport properties of l-LV and d-LV, and compared the efficacy of l-LV with d-LV to potentiate 5FU-mediated thymidylate synthase (TS) inhibition. Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn).

Results:

l-LV displayed an 8-fold and 3.5-fold higher substrate affinity than d-LV for the reduced folate carrier (RFC/SLC19A1) and proton coupled folate transporter (PCFT/SLC46A1), respectively. In selected colon cancer cell lines, the greatest enhanced efficacy of 5FU was observed for l-LV (2-fold) followed by the racemic mixture, whereas d-LV was ineffective. The cytotoxicity of antifolates in lymphoma and various solid tumor cell lines could be protected very efficiently by l-LV but not by d-LV. This protective effect of l-LV was dependent on cellular RFC expression as corroborated in RFC/PCFT-knockout and RFC/PCFT-transfected cells. Assessment of TS activity in situ showed that TS inhibition by 5FU could be enhanced by l-LV and dl-LV and only partially by d-LV. However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV.

Conclusion:

In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Suiza

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Front Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Suiza