Assessment of resistance induction to cytosine arabinoside following transfer and overexpression of the deoxycytidylate deaminase gene in vitro.
Recent attempts to protect hematopoietic progenitor cells from cytarabine (ara-C)-induced toxicity by transfer of the cytidine deaminase (CDD) gene resulted in efficient in vitro inducibility of ara-C resistance. Another enzyme involved in intracellular ara-CTP inactivation is the deoxycytidylate deaminase (dCMPD). We therefore transfected the human dCMPD cDNA gene into murine fibroblasts and investigated the relationship of forced dCMPD expression and resistance induction to ara-C. Several cell lines were established which demonstrated a 1.7-3.5-fold increase in cellular dCMPD activity and an up to 2-fold increase in the IC50 value of ara-C. However, increases in dCMPD activities did not show a positive linear correlation with the induction of ara-C resistance. In addition, CD34 + hematopoietic progenitor cells revealed the highest endogenous dCMPD enzyme levels among different human hematopoietic cells. Thus, despite the documented role for dCMPD in ara-CTP inactivation of certain cell types, these results suggest that the dCMPD gene may prove less useful than the CDD gene as a therapeutic target in attempts to attenuate ara-C-induced bone marrow toxicity.
Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School.
J K
JK
Schröder
M
M
Seidelmann
H C
HC
Kirch
S
S
Seeber
J
J
Schütte
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000201:enzymology; D003561:Cytarabine / Q000494:pharmacology; D003844:DCMP Deaminase / Q000096:biosynthesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice
D003561:Cytarabine; D003844:DCMP Deaminase