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 hum an CDD cDNA gene into murine fibroblast cells and examined the effect of increased CDD expression on the cellular resistance to ara-C. Sever al 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 o f ara-C, these cells maintained unaltered morphology and growth charac teristics as compared with parental cells and mock-transfected control s. 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 constitu tive overexpression of the CDD gene correlates with increased ara-C re sistance and thus may prove useful in considering attempts to attenuat e ara-C-induced toxicity on hematopoietic progenitor cells.