In experimental tumor systems, both in vitro and in vivo, the combinations of methotrexate (MTX) and 5-fluorouracil (FUra) have been reported to produce additive and synergistic as well as antagonistic antitumor effects. The sequence of administration of MTX and FUra is a critical determinant of efficacy. Synergy has been observed when tumor bearing animals or tumor cells in culture were exposed to MTX prior to FUra. Mechanisms of synergy of sequential MTX and FUra appear to be several. MTX and dihydrofolate polyglutamate derivatives enhance the binding of the active metabolite of FUra, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), to thymidylate (dTMP) synthetase by substituting for the natural cofactor 5,10-methylene tetrahydrofolate (5, 10-CH2FH4). Also MTX pretreatment increases the levels of intracellular 5-phosphoribosyl-1-pyrophosphate (PRPP) as a consequence of the inhibition of purine biosynthesis, resulting in increased FUra nucleotide formation via orotate phosphoribosyltransferase. Both active metabolites of FUra, FdUMP and 5-fluorouridine-5'-triphosphate (FUTP), are increased and might contribute to cell kill. FUTP is incorporated into RNA. In addition, dUTP is incorporated into DNA when dUMP levels increase as a consequence of MTX and/or FUra treatment. Based on experimental data, preliminary clinical studies of sequential MTX and FUra have been carried out demonstrating effectiveness in the treatment of advanced head and neck, breast, and colorectal cancer. Optimal drug doses, interval of drug administration and frequency of treatment have not yet been established. The effect of sequencing on normal tissues must also be considered. The sequential combination of MTX and FUra merits further evaluation as first line therapy in responsive tumors, and in other tumors responsive at least to one of the two drugs, when conventional chemotherapy has failed.

Sequential methotrexate and 5-fluorouracil: Biochemical pharmacology and therapeutic use / Mini E.; Bertino J.R.. - In: CHEMIOTERAPIA. - ISSN 0392-906X. - STAMPA. - 2:(1983), pp. 147-162.

Sequential methotrexate and 5-fluorouracil: Biochemical pharmacology and therapeutic use

Mini E.;
1983

Abstract

In experimental tumor systems, both in vitro and in vivo, the combinations of methotrexate (MTX) and 5-fluorouracil (FUra) have been reported to produce additive and synergistic as well as antagonistic antitumor effects. The sequence of administration of MTX and FUra is a critical determinant of efficacy. Synergy has been observed when tumor bearing animals or tumor cells in culture were exposed to MTX prior to FUra. Mechanisms of synergy of sequential MTX and FUra appear to be several. MTX and dihydrofolate polyglutamate derivatives enhance the binding of the active metabolite of FUra, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), to thymidylate (dTMP) synthetase by substituting for the natural cofactor 5,10-methylene tetrahydrofolate (5, 10-CH2FH4). Also MTX pretreatment increases the levels of intracellular 5-phosphoribosyl-1-pyrophosphate (PRPP) as a consequence of the inhibition of purine biosynthesis, resulting in increased FUra nucleotide formation via orotate phosphoribosyltransferase. Both active metabolites of FUra, FdUMP and 5-fluorouridine-5'-triphosphate (FUTP), are increased and might contribute to cell kill. FUTP is incorporated into RNA. In addition, dUTP is incorporated into DNA when dUMP levels increase as a consequence of MTX and/or FUra treatment. Based on experimental data, preliminary clinical studies of sequential MTX and FUra have been carried out demonstrating effectiveness in the treatment of advanced head and neck, breast, and colorectal cancer. Optimal drug doses, interval of drug administration and frequency of treatment have not yet been established. The effect of sequencing on normal tissues must also be considered. The sequential combination of MTX and FUra merits further evaluation as first line therapy in responsive tumors, and in other tumors responsive at least to one of the two drugs, when conventional chemotherapy has failed.
2
147
162
Mini E.; Bertino J.R.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1285747
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