Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells

Giuseppe S A Longo, Richard Gorlick, William P. Tong, Emine Ercikan, Joseph R. Bertino

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Previous work showed that acute myelocytic leukemia blasts accumulate less long chain polyglutamates of methotrexate (MTX) than acute lymphocytic leukemia blasts when incubated with this radio labeled antifolate. This difference likely explains the increased sensitivity of lymphoid leukemias to short-term exposure of MTX as compared with myeloid leukemias. In this study, we examined the basis for differences between long chain MTX polyglutamate accumulation between different leukemia cell types using both leukemia cell lines and blasts freshly isolated from blood of leukemic patients. The major difference found between leukemia cells that accumulate long chain polyglutamates and those that do not were differences in K(m) values for the enzyme folylpolyglutamate synthetase. K(m) values did not change with partial purification of this enzyme, indicating that interfering substances in crude lysates were not responsible for this difference. We postulate that there may be differences in the properties of this enzyme related to tissue specific expression. In contrast to MTX, both Tomudex (Zeneca Pharmaceuticals, Wilmington, DE) and 1843U89, potent inhibitors of thymidylate synthetase, have low K(m)s for folylpolyglutamate synthetase, and polyglutamate forms of these inhibitors are accumulated to the same degree in both myeloid and lymphoid acute leukemia cells, paralleling the equivalent cytotoxicity found between myeloid and lymphoid leukemia cell lines. Based on these results, we believe a clinical trial of Tomudex in patients with acute myeloid leukemia is warranted.

Original languageEnglish (US)
Pages (from-to)1241-1245
Number of pages5
JournalBlood
Volume90
Issue number3
StatePublished - Aug 1 1997
Externally publishedYes

Fingerprint

Folic Acid Antagonists
Acute Myeloid Leukemia
Polyglutamic Acid
Lymphoid Leukemia
Leukemia
Myeloid Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate
Enzymes
Cells
Cell Line
Thymidylate Synthase
Cytotoxicity
Radio
Purification
Blood
Clinical Trials
Lymphocytes
Tissue
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology

Cite this

Longo, G. S. A., Gorlick, R., Tong, W. P., Ercikan, E., & Bertino, J. R. (1997). Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells. Blood, 90(3), 1241-1245.

Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells. / Longo, Giuseppe S A; Gorlick, Richard; Tong, William P.; Ercikan, Emine; Bertino, Joseph R.

In: Blood, Vol. 90, No. 3, 01.08.1997, p. 1241-1245.

Research output: Contribution to journalArticle

Longo, GSA, Gorlick, R, Tong, WP, Ercikan, E & Bertino, JR 1997, 'Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells', Blood, vol. 90, no. 3, pp. 1241-1245.
Longo GSA, Gorlick R, Tong WP, Ercikan E, Bertino JR. Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells. Blood. 1997 Aug 1;90(3):1241-1245.
Longo, Giuseppe S A ; Gorlick, Richard ; Tong, William P. ; Ercikan, Emine ; Bertino, Joseph R. / Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells. In: Blood. 1997 ; Vol. 90, No. 3. pp. 1241-1245.
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