PMID: 8958187Jan 1, 1996Paper

Exploitation of folate and antifolate polyglutamylation to achieve selective anticancer chemotherapy

Investigational New Drugs
J J McGuireJ Galivan

Abstract

Synthesis of poly(gamma-glutamate) metabolites of natural folates and antifolates is a critical process. Folypolyglutamates are essential for cell proliferation. Polyglutamates of glutamate (Glu)-containing antifolates are often critical for their cytotoxic action and are relevant to antifolate resistance. However, the role of polyglutamate synthesis in selectivity is less clear. We have undertaken a research program to further define the significance of polyglutamate metabolism and to devise ways to exploit this metabolism to achieve greater therapeutic selectivity in cancer chemotherapy. This article briefly reviews several approaches tested thus far. Inhibition of folypolyglutamate synthesis should lead to cell death. Current ornithine (Orn)-containing folate-based inhibitors of the enzyme responsible for their synthesis, folypolyglutamate synthetase (FPGS), are poorly transported, apparently because of interference by the protonated delta-amine. Replacement of Orn with 4, 4-difluoroOrn, the delta-amine of which has a much lower pKa and is thus less protonated at physiological pH, was explored. Since it is unclear how polyglutamylation contributes to selectivity, we explored generic means either to eliminate or to enhance po...Continue Reading

References

Jan 1, 1993·Advances in Experimental Medicine and Biology·A L JackmanF T Boyle
Jan 1, 1994·Advances in Experimental Medicine and Biology·A L JackmanF T Boyle

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Citations

Sep 14, 2016·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Shachar RazYehuda G Assaraf
Feb 14, 2016·Microbiology·Laurence PrunettiValérie de Crécy-Lagard
Jan 3, 2001·Journal of Bacteriology·Y WeiR A LaRossa
Apr 17, 2021·ACS Pharmacology & Translational Science·Christine R CuthbertsonNouri Neamati

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