Acquired drug resistance is the major obstacle to successful treatment of many cancers. Knowledge of the mechanisms of resistance may lead to therapeutic plans to circumvent or reverse the resistance. Resistance to cytosine arabinoside (araC) is often associated with a decrease in deoxycytidine kinase (dCK) activity, the rate limiting enzymatic step in the activation of araC to araCTP. We have now isolated human cDNA clones for dCK. The overall goal of this proposal is to use these probes to characterize the enzyme and the control of its expression in cell lines that are sensitive and resistant to araC.
Specific Aims are to : 1. Characterize the coding sequence of human dCK and deduce its amino acid sequence. 2. Express human dCK in microorganisms and tissue culture cells and raise antibodies to it. 3. Identify important genomic sequences involved in the transcriptional regulation of human dCK. 4. Determine whether sensitivity to araC is related to the level of dCK expression in human cell lines.
| Huang, S H; Tomich, J M; Wu, H et al. (1989) Human deoxycytidine kinase. Sequence of cDNA clones and analysis of expression in cell lines with and without enzyme activity. J Biol Chem 264:14762-8 |
