Recombinant gene products of two natural variants of the human cytidine deaminase gene confer different deamination rates of cytarabine in vitro.
The recent cloning of human cytidine deaminase (CDD) revealed two variants with a nonconservative amino acid deviation (Gln<-->Lys) at codon 27 within a region of structural homology to a core domain of bacterial CDDs. We here confirm the occurrence of both CDD sequences by cDNA cloning and show that at cytarabine (ara-C) concentrations of 1x10(-8) to 2x10(-2) M, the recombinant enzyme corresponding to the Lys-carrying natural variant (CDD-2) exerts a 1.3- to 3.3-fold higher in vitro deamination rate of ara-C than the Gln-carrying enzyme (CDD-1). These results suggest that this genetic polymorphism contributes to the different deamination phenotypes of ara-C observed in vivo, and that investigation of CDD allelotype frequencies and their correlation with ara-C resistance in patients with acute leukemia may be warranted. In addition, our data may be relevant to recently considered CDD gene transfer strategies for the detoxification of hematopoietic stem cells during high-dose therapy with cytosine nucleoside analogs.
Kirch
H C
HC
Institute of Molecular Biology (Cancer Research), University of Essen Medical School, West German Cancer Center.
Schröder
J
J
Hoppe
H
H
Esche
H
H
Seeber
S
S
Schütte
J
J
D003561:Cytarabine / Q000737:chemistry; D003562:Cytidine / Q000737:chemistry; D003564:Cytidine Deaminase / Q000737:chemistry* / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D003641:Deamination; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D011994:Recombinant Proteins / Q000737:chemistry*; D017422:Sequence Analysis, DNA
D018076:DNA, Complementary; D011994:Recombinant Proteins; D003561:Cytarabine; D003562:Cytidine; D003564:Cytidine Deaminase