γ-glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias

Giuseppe S A Longo, Richard Gorlick, William P. Tong, Silan Lin, Peter Steinherz, Joseph R. Bertino

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Decreased methotrexate (MTX) long-chain polyglutamate formation is associated with MTX resistance whereas high levels of MTX polyglutamate accumulation are found in the blasts of leukemia patients who respond to therapy and have improved outcome. The steady-state level of long-chain MTX polyglutamates depends on the balance of activities of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamates to MTX in a y-carboxyl linkage, and -y-glutamyl hydrolase (GGH) or conjugase, which sequentially removes the terminal glutamate residue of MTX polyglutamates. FPGS and GGH activities as well as the formation of total and long-chain MTX polyglutamates were measured after incubation with [3H]MTX in 15 blast samples from patients with acute leukemias (myeloid and lymphoid). The ratio between GGH and FPGS activities was better at predicting the amount of polyglutamate accumulated in the 24-h [3H]MTX assay compared to the determination of either activity alone. The linear regression curve relating the relative levels of long-chain polyglutamates/total polyglutamates with the ratio of GGH/FPGS showed an r value of 0.81 (P < 0.001). These data suggest that the evaluation of both these enzymes at diagnosis may be used as a predictor of MTX polyglutamylation and therefore for response to MTX therapy and outcome.

Original languageEnglish (US)
Pages (from-to)259-263
Number of pages5
JournalOncology Research
Volume9
Issue number5
StatePublished - 1997
Externally publishedYes

Fingerprint

Hydrolases
Methotrexate
Leukemia
Polyglutamic Acid
gamma-Glutamyl Hydrolase
Glutamates
Enzymes
folylpolyglutamate synthetase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Glutamic Acid
Linear Models
methotrexate polyglutamate
Therapeutics

Keywords

  • γ-giutamyl hydrolase
  • Acute lymphocytic leukemia
  • Acute myelocytic leukemia
  • Folypolyglutamate synthetase
  • Methotrexate
  • Methotrexate polyglutamates

ASJC Scopus subject areas

  • Cancer Research

Cite this

Longo, G. S. A., Gorlick, R., Tong, W. P., Lin, S., Steinherz, P., & Bertino, J. R. (1997). γ-glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. Oncology Research, 9(5), 259-263.

γ-glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. / Longo, Giuseppe S A; Gorlick, Richard; Tong, William P.; Lin, Silan; Steinherz, Peter; Bertino, Joseph R.

In: Oncology Research, Vol. 9, No. 5, 1997, p. 259-263.

Research output: Contribution to journalArticle

Longo, GSA, Gorlick, R, Tong, WP, Lin, S, Steinherz, P & Bertino, JR 1997, 'γ-glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias', Oncology Research, vol. 9, no. 5, pp. 259-263.
Longo, Giuseppe S A ; Gorlick, Richard ; Tong, William P. ; Lin, Silan ; Steinherz, Peter ; Bertino, Joseph R. / γ-glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. In: Oncology Research. 1997 ; Vol. 9, No. 5. pp. 259-263.
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