Cytosine arabinoside deamination

Laliberte, J., Marquez, V.E. and Momparler, R.L. (1992) Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2 -deoxycytidine by human cytidine deaminase. 

The distribution and disposition of a drug in the body result from a complex set of physiological processes and biochemical interactions. In principle, it is possible to describe these processes and interactions in mathematical terms and, if sufficient data are available, to predict the time course of drug and metabolite(s) in different species and at specific anatomic sites (15). A physiological pharmacokinetic model was developed to predict the deamination of cytosine arabinoside (ARA-C) in humans from enzyme parameters determined from homogenates of human tissue (16). ARA-C is converted to its inactive metabolite, uracil arabinoside (ARA-U) by cytidine deaminase, the activity of which varies substantially among tissues. 

The introduction of an azido substituent on the C-2 position of cytosine arabinoside (ara-C) (149) or adenosine arabinoside (ara-A) (154) has been found to confer favourable properties to these antimetabolites. Ara-C, one of the most effective drugs for the treatment of human acute myeloblastic leukaemia [176], is subject to rapid metabolic deamination, by deoxycytid-ine deaminase, to the inactive uridine derivative ara-U (152) Scheme 3.5), and the drug has a half-life of approximately 12 minutes in man [177]. Efforts to circumvent this problem by modifying the 2 -arah/ o-position led... 

Cytosine arabinoside is enzymatically deaminated in the liver. The resulting product, uracil arabinoside, no longer possesses antileukaemia or antiviral activity [291, 292, 340, 341]. A variety of cytosine derivatives have been studied as deaminase inhibitors. The most active of these was a 4-hydroxylamino derivative, iV -hydroxy-5-methyl-2 -deoxycytidine [342]. 

This enzyme is found in various animal tissues and that from sheep liver has been purified 280-fold 11). Both cytidine and deoxycytidine are deaminated, as are the 5-halogen derivatives (e.g., 5-fluoro-deoxycytidine). Cytosine, cytidylate, and deoi i idylate are not deaminated by this enzyme. Cytosine arabinoside (iHS-D-arabinofurano lcytosine), which has an important use in the treatment of human neoplastic disease, is a substrate for cytidine deaminase in the human, this compound is rapidly deaminated to yield the inactive uracil arabinoside 12). Cytidine deaminase is very active in E. ccli and S. typhimwrium, but is absent from yeasts and lactobacilli (7). The E. coli enzyme has been partly purified IS) and has a specificity similar to that of the animal enzyme. The E. coli enzyme deaminates 5-methyldeoxycytidine, enabling this compound to support the growth of a thymine-requiring E. coli mutant 11. ... 

G.W. Camiener and C.G. Smith, Studies of the enzymatic deamination of cytosine arabinoside-I. 

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