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, has the ability to metabolize L-2-oxothiazolidine-4-carboxylic acid (OTC) to cysteine, and thereby increase intracellular glutathione (GSH) levels. This strategy of GSH elevation can be potentially exploited to reduce normal tissue toxicity of anticancer agents, provided that sufficient differences exist in OPase levels between normal and malignant tissues. In this study, therefore, we quantitated OPase activity in primary 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 examined was kidney > lung, breast and colon > ovary. OPase activity was present in all 37 tumor samples, but at variable levels. Tumor OPase levels were generally equivalent to those in their normal tissue counterparts, with the notable exception of Wilms' tumors, which had markedly lower levels than normal kidney (P < 0.02). However, when 14 matched tumor and adjacent normal tissues were compared, OPase levels were significantly higher in normal specimens than tumors for individual patients (P < 0.005). These higher normal tissue/tumor OPase ratios suggest that OTC may be useful in decreasing normal tissue toxicity, at least, for some tissues during cancer therapy.
Srivenugopal
K S
KS
Department of Experimental Pediatrics, University of Texas, M.D. Anderson Cancer Center, Houston 77030, USA.
Ali-Osman
F
F
D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology*; D011355:Prodrugs / Q000378:metabolism; D011752:Pyroglutamate Hydrolase / Q000378:metabolism*; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles / Q000378:metabolism; D053778:Thiazolidines
D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; D011752:Pyroglutamate Hydrolase; D003545:Cysteine; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid