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Leukaemic blasts differ from normal bone marrow mononuclear cells and CD34 + haemopoietic stem cells in their metabolism of cytosine arabinoside
Author(s) -
Braess J.,
Wegendt C.,
FeuringBuske M.,
Riggert J.,
Kern W.,
Hiddemann W.,
Schleyer E.
Publication year - 1999
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.1999.01338.x
Subject(s) - bone marrow , cd34 , cytarabine , peripheral blood mononuclear cell , stem cell , biology , progenitor cell , cytosine , haematopoiesis , cytotoxicity , cancer research , microbiology and biotechnology , leukemia , biochemistry , immunology , in vitro , dna
Different metabolites of cytosine arabinoside (AraC) contribute to its cytotoxicity including incorporation of AraCTP into DNA, the incorporation of AraUMP into RNA, inhibition of polymerase α and β (AraCMP/CTP), an impairment of repair mechanisms (AraCTP), alterations of phospholipid metabolism (AraCDP‐choline), a direct membrane interaction (AraC), the alteration of signal transduction pathways (AraCDP‐choline, AraCTP) and the induction of apoptosis. Since little is known about the potential differences in AraC metabolism between leukaemic blasts and normal haemopoietic progenitor cells, the formation of all known AraC metabolites was determined in bone marrow samples from patients with acute myeloid leukaemia (AML), healthy volunteers and specimens of cellsorted CD34 + haemopoietic stem cells. Highly significant differences were found for phosphorylated AraC metabolites (AraCMP, ‐CDP, ‐CTP, AraUMP) between AML and normal mononuclear bone marrow (ng/10 7 cells respectively 1.30 v 2.66; 2.65 v 7.50; 33.68 v 99.0; 1.18 v 5.70). The highest differences were found for formation of AraCDP‐choline (3.75 v 12.86) which might be relevant for the high efficacy of high‐dose AraC regimens. In contrast, no differences were found in the deamination product AraU (2.01 v 2.91). Only minute amounts of phosphorylated AraU derivatives were detected, providing an explanation for the lacking contribution of AraU to cytosine arabinoside cytotoxicity. Results in normal CD34 + haemopoietic stem cells did not differ significantly from normal bone marrow mononuclear cells and therefore justify their use as a surrogate in determining AraC‐induced haematotoxicity. These data suggest a metabolic basis for the relative selectivity of AraC cytotoxicity for AML blasts and provide a means to determine the role of different metabolites and their related mechanism of action for overall AraC cytotoxicity.