ACTIVITY AND DISTRIBUTION OF THE CYSTEINE PRODRUG ACTIVATING ENZYME, 5-OXO-L-PROLINASE, IN HUMAN NORMAL AND TUMOR-TISSUES

5-Oxo-L-prolinase (OPase), a key enzyme of the gamma-glutamyl cycle, h as the ability to metabolize L-2-oxothiazolidine-4-carboxylic acid (OT C) to cysteine, and thereby increase intracellular glutathione (GSH) l evels. This strategy of GSH elevation can be potentially exploited to reduce normal tissue toxicity of anticancer agents, provided that suff icient differences exist in OPase levels between normal and malignant tissues. in this study, therefore, we quantitated OPase activity in pr imary specimens of matched and unmatched human normal and tumor (lung, breast, kidney, colon and ovary) tissues using a newly developed non- radioactive OPase assay, based on the production of cysteine from OTC. The rank order of OPase activity in extracts of 24 normal tissues exa mined was kidney > lung, breast and colon > ovary. OPase activity was present in all 37 tumor samples, but at variable levels. Tumor OPase l evels were generally equivalent to those in their normal tissue counte rparts, with the notable exception of Wilms' tumors, which had markedl y lower levels than normal kidney (P < 0.02). However, when 14 matched tumor and adjacent normal tissues were compared, OPase levels were si gnificantly higher in normal specimens than tumors for individual pati ents (P < 0.005). These higher normal tissue/tumor OPase ratios sugges t that OTC may be useful in decreasing normal tissue toxicity, at leas t, for some tissues during cancer therapy. (C) 1997 Elsevier Science I reland Ltd.