Constitutive overexpression of the cytidine deaminase gene confers resistance to cytosine arabinoside in vitro.
In search of potential therapeutic targets for enhancing the cellular detoxification of cytosine-arabinoside (ara-C), we transfected the human CDD cDNA gene into murine fibroblast cells and examined the effect of increased CDD expression on the cellular resistance to ara-C. Several cell lines were established which consistently demonstrated a 2.5-3.0-fold increase in cellular CDD activity and exhibited an up to 3.0-3.5-fold increase in the IC50 value of ara-C with regard to inhibition of cell proliferation or DNA synthesis, respectively. In the absence of ara-C, these cells maintained unaltered morphology and growth characteristics as compared with parental cells and mock-transfected controls. In addition, we examined the CDD and dCK activity in hematopoietic cells and found CD34+ hematopoietic progenitor cells to reveal a low ratio of CDD/dCK activity. Together, these data suggest that constitutive overexpression of the CDD gene correlates with increased ara-C resistance and thus may prove useful in considering attempts to attenuate ara-C-induced toxicity on hematopoietic progenitor cells.
Schröder
J K
JK
Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen, Germany.
Kirch
C
C
Flasshove
M
M
Kalweit
H
H
Seidelmann
M
M
Hilger
R
R
Seeber
S
S
Schütte
J
J
D000328:Adult; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003561:Cytarabine / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D015870:Gene Expression; D018922:HL-60 Cells / Q000187:drug effects / Q000201:enzymology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D014162:Transfection
D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D003561:Cytarabine; D003564:Cytidine Deaminase