Cytidine and deoxycytidylate deaminase inhibition by uridine analogs.
Cytidine deaminase, an enzyme found in the supernatant fluid of hepatocytes, granulocytes and tumor cells, and in plasma, degrades the antitumor agents cytosine arabinoside and 5-azacytidine. Uridine and its analogs, 3-deazauridine, 5-bromodeoxyuridine, 5-fluorodeoxyuridine and 6-azauridine, were found to competitively inhibit cytidine deaminase; the most potent inhibitor was 3-deazauridine (K(i) = 1.9 x 10(-5) M). In addition, deoxycytidylate deaminase, which degrades cytosine arabinoside monophosphate to the inactive uracil arabinoside monophosphate (K(m) = 9 x 10(-4) M), was competitively inhibited by 3-deazauridine monophosphate, as well as by the nucleotides of other uridine analogs. These results suggest that uridine analogs such as 3-deazauridine may have value in protecting cytosine arabinoside, 5-azacytidine and their monophosphate nucleotides from degration by neucleoside and nucleotide deaminases.
Clinical Pharmacology Branch, Clinical Oncology Program, and Laboratory of Medicinal Chemistry and Biology, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20205, USA.
J C
JC
Drake
K R
KR
Hande
R W
RW
Fuller
B A
BA
Chabner
D015092:3-Deazauridine / Q000378:metabolism; D001380:Azauridine / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D003564:Cytidine Deaminase / Q000032:analysis / Q000037:antagonists & inhibitors*; D003844:DCMP Deaminase / Q000032:analysis / Q000037:antagonists & inhibitors*; D005467:Floxuridine / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D014529:Uridine / Q000031:analogs & derivatives* / Q000378:metabolism
D005467:Floxuridine; D015092:3-Deazauridine; D001380:Azauridine; D003844:DCMP Deaminase; D003564:Cytidine Deaminase; D001973:Bromodeoxyuridine; D014529:Uridine