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Some Properties of Uridine-Cytidine Kinase from a Human Malignant Lymphoma¹

Division of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101

Uridine-cytidine kinase has been partially purified from a malignant human lymphoma, and some of its properties have been described. The apparent Michaelis constants for uridine and adenosine 5'-triphosphate are 7 x 10^–5 and 4 x 10^–4 M, respectively. Maximal enzyme activity is observed between pH 6.5 and 8.5, and temperatures of incubation are observed between 37 and 42°. The enzyme requires Mg²⁺ for full enzymatic activity and exists in two isozymic forms, as indicated by isoelectric focusing and column chromatography on Sepharose 6B. The roles of these two isozymes, i.e., the adult (I) and the embryonic (II) forms, are not yet clear; conceivably, however, they may have relevance to the problem of the development of resistance to chemotherapeutic analogs that require uridinecytidine kinase for their "activation."

Potent inhibitors (pyrazofurin and N-phosphonacetyl-L-aspartic acid) of the biosynthesis de novo of uridine 5'-monophosphate have not inhibited significantly the growth of other than a relatively few experimental tumors. Most neoplastic cells also can derive their essential supplies of uridine 5'-monophosphate by one or another route, especially through the salvage of uridine and cytidine, as catalyzed by uridine-cytidine kinase. No effective inhibitor of this key enzyme in the salvage pathway has been reported. Among a variety of compounds (20 substances) so far examined by us for their possible ability to interfere with the phosphorylation of [5-³H]uridine by adenosine 5'-triphosphate, as catalyzed by uridine-cytidine kinase, none is a powerful inhibitor of this enzyme, although leads for future development have been obtained. In the meantime, information concerning the uridine-cytidine kinase activity of a variety of murine and human neoplasms (particularly of colorectal origin), as well as in normal tissues, is being expanded; these findings may contribute to the design and prospective syntheses of potential chemotherapeutic agents, functioning as inhibitor of the salvage of uridine and cytidine.

¹ This investigation was supported by the Whitehall Foundation, Grant CA21677 from the National Cancer Institute, Department of Health, Education, and Welfare, and American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed, at St. Jude Children's Research Hospital, P. O. Box 318, Memphis, Tenn. 38101.

Received 1/24/79. Accepted 5/ 8/79.