Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells

Abstract

Previous work showed that acute myelocytic leukemia that interfering substances in crude lysates were not responblasts accumulate less long chain polyglutamates of methosible for this difference. We postulate that there may be trexate (MTX) than acute lymphocytic leukemia blasts when differences in the properties of this enzyme related to tissue incubated with this radiolabeled antifolate. This difference specific expression. In contrast to MTX, both Tomudex (Zenlikely explains the increased sensitivity of lymphoid leukeeca Pharmaceuticals, Wilmington, DE) and 1843U89, potent mias to short-term exposure of MTX as compared with myinhibitors of thymidylate synthetase, have low K m s for folyleloid leukemias. In this study, we examined the basis for polyglutamate synthetase, and polyglutamate forms of differences between long chain MTX polyglutamate accuthese inhibitors are accumulated to the same degree in both mulation between different leukemia cell types using both myeloid and lymphoid acute leukemia cells, paralleling the leukemia cell lines and blasts freshly isolated from blood equivalent cytotoxicity found between myeloid and of leukemic patients. The major difference found between lymphoid leukemia cell lines. Based on these results, we leukemia cells that accumulate long chain polyglutamates believe a clinical trial of Tomudex in patients with acute and those that do not were differences in K m values for the myeloid leukemia is warranted. enzyme folylpolyglutamate synthetase. K m values did not ᭧ 1997 by The American Society of Hematology. change with partial purification of this enzyme, indicating humidified atmosphere in RPMI 1640 media containing 10% fetal