Determinants of antifolate cytotoxicity

Folylpolyglutamate synthetase activity during cellular proliferation and development

Julio Barredo, Richard G. Moran

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Previous studies have documented the metabolism of a broad range of folate antimetabolites to polyglutamate derivatives by the enzyme folylpoly-γ-glutamate synthetase (FPGS). The activity of the more recently developed classes of antifolates directed against thymidylate synthase and de novo purine synthesis is sufficiently dependent on polyglutamation that these compounds should be specifically cytotoxic to any normal or malignant proliferating cell expressing this enzyme. We have studied the patterns of expression of FPGS in mammalian cells and tissues during rapid growth, growth arrest, differentiation, and embryonic development. During embryogenesis in the rat, FPGS levels in liver and brain were higher during the period of proliferative activity and then dropped to a level characteristic of the adult organs. However, the levels in liver were substantially higher than those in brain at any given time. This pattern was mimicked in mouse C3H 10T1/2 embryo fibroblast cells, in which FPGS activity decreased after cessation of growth but then remained at a lower steady state level during an extended period of postconfluent culture. Enzyme activity also dropped after the differentiation of human HL-60 promyelocytic leukemia cells. In a human homolog of these experimental systems, FPGS levels were below the limits of detection in circulating mature human hematopoietic cells of the granulocytic, lymphoblastic, and erythrocytic lineages. In striking contrast, substantial levels of FPGS were found in circulating lymphoblasts from eight patients with acute lymphoblastic leukemia. The levels of FPGS found in these transformed stem cells would help to explain the sensitivity of many acute lymphoblastic leukemias to folate antimetabolites. We concluded that expression of FPGS is regulated by at least two mechanisms, one of which is linked to proliferation and the other of which controls enzyme levels after differentiation and is tissue specific.

Original languageEnglish
Pages (from-to)687-694
Number of pages8
JournalMolecular Pharmacology
Volume42
Issue number4
StatePublished - Oct 1 1992
Externally publishedYes

Fingerprint

Folic Acid Antagonists
Ligases
Glutamic Acid
Cell Proliferation
Antimetabolites
Enzymes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Folic Acid
Embryonic Development
Growth
Polyglutamic Acid
Thymidylate Synthase
folylpolyglutamate synthetase
Inbred C3H Mouse
Liver
Brain
Limit of Detection
Leukemia
Stem Cells
Embryonic Structures

ASJC Scopus subject areas

  • Pharmacology

Cite this

Determinants of antifolate cytotoxicity : Folylpolyglutamate synthetase activity during cellular proliferation and development. / Barredo, Julio; Moran, Richard G.

In: Molecular Pharmacology, Vol. 42, No. 4, 01.10.1992, p. 687-694.

Research output: Contribution to journalArticle

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