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Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells.
MedLine Citation:
PMID:  9242558     Owner:  NLM     Status:  MEDLINE    
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 radiolabeled 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 Km values for the enzyme folylpolyglutamate synthetase. Km 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 Kms 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.
G S Longo; R Gorlick; W P Tong; E Ercikan; J R Bertino
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Blood     Volume:  90     ISSN:  0006-4971     ISO Abbreviation:  Blood     Publication Date:  1997 Aug 
Date Detail:
Created Date:  1997-08-25     Completed Date:  1997-08-25     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1241-5     Citation Subset:  AIM; IM    
Department of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
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MeSH Terms
Acute Disease
Antimetabolites, Antineoplastic / metabolism*,  pharmacology
Drug Resistance, Neoplasm
Enzyme Inhibitors / metabolism*,  pharmacology
Folic Acid Antagonists / metabolism*,  pharmacology
HL-60 Cells / drug effects,  enzymology
Indoles / metabolism*,  pharmacology
Leukemia, Myeloid / metabolism*,  pathology
Methotrexate / metabolism*,  pharmacology
Neoplasm Proteins / antagonists & inhibitors,  isolation & purification,  metabolism*
Organ Specificity
Peptide Synthases / antagonists & inhibitors,  isolation & purification,  metabolism*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*,  pathology
Quinazolines / metabolism*,  pharmacology
Thiophenes / metabolism*,  pharmacology
Thymidylate Synthase / antagonists & inhibitors
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Enzyme Inhibitors; 0/Folic Acid Antagonists; 0/Indoles; 0/Isoindoles; 0/Neoplasm Proteins; 0/Quinazolines; 0/Thiophenes; 112887-68-0/raltitrexed; 139987-54-5/1843U89; 59-05-2/Methotrexate; EC Synthase; EC 6.3.2.-/Peptide Synthases; EC synthetase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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