Methods and pharmaceutical compositions for treating cancer
A composition and cancer technology, applied in the direction of drug combination, antineoplastic drugs, pharmaceutical formulations, etc., can solve the problem of PteGlu no high
Pending Publication Date: 2021-08-20
大卫马舒瓦尔
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However, CH 2 -H 4 High intracellular levels of PteGlu remain a problem: CH 2 -H 4 None of the intracellular levels of PteGlu were high enough for optimal inhibition of TS by FUra
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[0113] The active metabolite of 5-fluorouracil (FUra), fluorodeoxyuridine monophosphate (FdUMP), binds thymidylate synthase (TS) and CH 2 -H 4 PteGlu to form a ternary complex [FdUMP-TS-CH 2 -H 4 PteGlu], while inactivating TS (1-3). Over a wide concentration range, the stability of the complex increases with CH 2 -H 4 increased with increasing PteGlu levels (2, 3). Low concentrations of cofactors lead to dissociation of the complex and restoration of enzyme activity, resulting in a loss of the cytotoxic potency of the fluoropyrimidine. Supplementary exposure in vitro to high concentrations of N5-formyltetrahydropteroylglutamate (5-HCO-H 4 PteGlu; folinic acid; leucovorin) in cancer cell lines with FUra or fluorodeoxyuridine (FUdR) resulted in more ternary complex formation than with these fluoropyrimidines as single agents, leading to enhanced cytotoxic effects (4).
[0114] Based on these findings, investigators including our own have designed regimens combining FUra...
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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-HCO- H4PteGlu; 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 or pyridoxine 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.
Description
technical field [0001] The present invention relates to methods and pharmaceutical compositions for treating cancer in a subject in need thereof. Background technique [0002] Since its introduction in the 1950s by Heidelberg et al., the drug of choice for the treatment of metastatic colorectal carcinoma has been 5-fluorouracil (FUra), a fluorinated analog of uracil. [0003] Biochemical studies have demonstrated that the main route of action of FUra is through a complex metabolic pathway leading to the formation of 5-fluorodeoxyuridine monophosphate (FdUMP), a potent inhibitor of thymidylate synthase (TS). [0004] Mechanistically, it was confirmed that FdUMP forms a covalent ternary complex consisting of FdUMP, TS and 5,10-methylenetetrahydrofolate (CH 2 -H 4 PteGlu), accompanied by enzyme inhibition to inactivate TS. The stability of the complex depends on CH 2 -H 4 Concentration of PteGlu. Indeed, the rate of FdUMP dissociation from the ternary complex increases wi...
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IPC IPC(8): A61K31/4415A61K31/513A61K31/675A61K31/7068A61K31/7072A61P35/00
CPCA61K31/4415A61K31/513A61K31/675A61K31/7068A61K31/7072A61P35/00A61K2300/00A61K31/519A61K45/06
Inventor 大卫·马舒瓦尔
Owner 大卫马舒瓦尔