THE INFLUENCE OF 2-CHLORO-2'-DEOXYADENOSINE ON METABOLISM OF DEOXYADENOSINE IN HUMAN PRIMARY CNS LYMPHOMA

The effects of 2-chloro-2'-deoxyadenosine (2CdA) on the activity of en zymes important for the metabolism of deoxyadenosine were studied in l ysates prepared from human primary central nervous system (CNS) lympho mas and normal human lymphocytes. Strong inhibition (approximately 100 %) of the phosphorylation of deoxyadenosine to its deoxynucleotide pho sphate derivatives was produced in both systems in the presence of 2Cd A, which was phosphorylated concomitantly to 2-chloro-2'-deoxyAMP. Int erestingly, 2CdA was also found to be an inhibitor of the deamination of both deoxyadenosine (over 50%) and AMP (70%). These findings add to our understanding of the mechanisms of toxicity of this drug, especia lly considering that 2CdA is resistant to deamination by adenosine dea minase. These results challenge the existing theories of 2CdA toxicity , which have been limited to the formation of phosphate derivatives of 2CdA. The present in vitro studies have demonstrated that 2CdA also i nhibits both phosphorylation and deamination of deoxyadenosine (dAdo), suggesting that its mechanism of toxicity includes a block in dAdo me tabolic pathways. This has important implications for the perturbation of cell methylation, a functionality associated with, for example, ap optosis.