Cytidine Deaminase and the Development of Resistance to Arabinosyl Cytosine

THE effectiveness of arabinosyl cytosine (cytarabine: 1-β-D-arabinofuranosylcytosine, ‘Cytosar’, abbreviated to ara-C) in the treatment of human leukaemia can be correlated with the rate of uptake of the molecule in vitro¹ and its subsequent phosphorylation. In man, this nucleoside is also rapidly deaminated to produce arabinosyl uridine which has no therapeutic activity²: both liver and serum contain pyrimidine nucleoside deaminase³. Consequently the half-life of unchanged ara-C in human sera is brief (about 15 min^?1) (ref. 2). These characteristics suggest a relationship between cytidine deaminase and the susceptibility of the leukaemic cell to ara-C and we have found that initial therapeutic responses in human leukaemia are correlated with lower intracellular concentrations of deaminase than those present in non-responders., Furthermore, in sequential treatment schedules, increasing concentrations of deaminase are associated with markedly reduced susceptibility of the tumour cell to ara-C.