Enhancement of 5-fluorouracil cytotoxicity by pyridoxal 5’-phosphate and folinic acid in tandem

The invention relates to methods and pharmaceutical compositions for treating cancer in a subject in need thereof. The inventors thought that low activity of serine hydroxymethyl transferase (SHMT) due to poor pyridoxal 5'-phosphate (PLP) availability within cancer cells would result in insufficient growth inhibition in cancer cells exposed to 5-fluorouracil (FUra), as well as to FUra in combination with N5-formyl tetra hydro pteroylglutamate (5-HCOH4PteGlu; folinic acid). Cancer cell lines grown in vitro were exposed to FUra as a single agent and to FUra with folinic acid, in combination with high concentration PLP. The inventors demonstrated synergistic and additive interactions upon cytotoxicity of FUra by folinic acid and PLP combined in HT29, HCT116, and L1210 cancer cells. Murine studies of parenteral administration of pyridoxamine in high doses showed that intracellular PLP is augmented to levels close or greater than the Kd reported for binding of cofactor to SHMT, which suggests that modulation of the fluoropyrimidines by vitamin B6 could be achieved in vivo. Thus, the present invention relates to an antitumor pharmaceutical combination comprising (i) a fluoropyrimidine, (ii) a B6 vitamer, and optionally (iii) a folate, and the use of said combination in the treatment of cancer in a subject in need thereof.

Keywords: combination
Patent Application number: EP18305661.3
Publications:
J Pharmacol Exp Ther. 2018 Aug;366(2):238-243. doi: 10.1124/jpet.118.249367. Epub 2018 Jun 1.

Reference:

BIO17660-T1

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Anne COCHI
Anne COCHI
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Patent filling date: 30-05-2018

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