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 enzymes important for the metabolism of deoxyadenosine were studied in lysates prepared from human primary central nervous system (CNS) lymphomas and normal human lymphocytes. Strong inhibition (approximately 100%) of the phosphorylation of deoxyadenosine to its deoxynucleotide phosphate derivatives was produced in both systems in the presence of 2CdA, which was phosphorylated concomitantly to 2-chloro-2'-deoxyAMP. Interestingly, 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, especially considering that 2CdA is resistant to deamination by adenosine deaminase. 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 inhibits both phosphorylation and deamination of deoxyadenosine (dAdo), suggesting that its mechanism of toxicity includes a block in dAdo metabolic pathways. This has important implications for the perturbation of cell methylation, a functionality associated with, for example, apoptosis.
Fabianowska-Majewska
K
K
Dept. of General Chemistry, Medical Univ. of Lódź, Poland.
Tybor
K
K
Duley
J
J
Simmonds
A
A
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000228:Adenine Phosphoribosyltransferase / Q000378:metabolism; D000243:Adenosine Deaminase / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D043383:Adenosylhomocysteinase; D017209:Apoptosis / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D017338:Cladribine / Q000494:pharmacology*; D003641:Deamination / Q000187:drug effects; D003839:Deoxyadenosines / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D000249:Adenosine Monophosphate; D017338:Cladribine; D000228:Adenine Phosphoribosyltransferase; D006867:Hydrolases; D015720:5'-Nucleotidase; D043383:Adenosylhomocysteinase; D000243:Adenosine Deaminase