GSH levels in a human lung fibroblast cell line compared to a human lung adenocarcinoma cell line is achievable by OTZ

tion from toxic oxygen species and detoxification of various xenobiotics (8, 9). The ability to modulate cellular GSH levels to probe the importance of this tripeptide in various drug or radiation interactions hascome from the elegant work of Meis ter and Griffith (10) and Williamson et a!. (11) who have introduced compounds that either inhibit or stimulate GSH synthesis. When GSH synthesis is inhibited by BSO (10), the effective ness of several chemotherapy drugs has been increased (1, 2); conversely, when GSH levels were elevated by OTZ, a com pound that stimulates GSH synthesis (1 1), protection against bleomycin and Adriamycin has been reported (1, 2). In a recent study from our laboratory, it was observed that human tumor cell lines generally had higher levels of cellular GSH than did normal human fibroblasts (12). This finding was of particular interest in light of previous studies from our laboratory demonstrating that GSH synthesis in Chinese ham ster cells was stimulated by OTZ. OTZ is converted intracel lularly by the action of 5-oxo-L-prolinase to cysteine (I 1). The cysteine is then rapidly utilized in the GSH cycle with subse quent elevation in GSH levels (1, 2, 12—1 5). When Chinese hamster cells are exposed to OTZ, there is a rapid elevation in GSH; however, by 2 h, GSH levels plateau at approximately 200% of control. The leveling off in GSH levels is probably a result of GSH feedback inhibition of †̃y-glutamylcysteinesyn thetase and thus regulation of the GSH cycle (15). We ques tioned if the relatively high GSH levels observed in the human tumor lines represented maximum synthesis and whether these tumor cells could not be stimulated to produce higher levels of GSH by OTZ treatment; additionally, the normal fibroblast lines which are low in GSH compared to the tumor lines might possibly be stimulated by OTZ treatment. Should such differ ential manipulation in GSH levels in tumor versusnormal cells bepossible, then the possibility ofselective protection of normal cells to selected drugs may be feasible; conversely, due to the relatively high levelsofGSH in thesetumor lines, it also seemed reasonableto question ifGSH synthesiswere inhibited by BSO, would GSH levels drop faster in the normal versusthe tumor cell line? The present study demonstrates that selective elevation in GSH levels in a human lung fibroblast cell line compared to a human lung adenocarcinoma cell line is achievable by OTZ treatment; additionally, the relative rate of GSH depletion by BSO treatment was observed to be faster in the normal versus the tumor cell line. The subsequentresponseto selectedchem otherapy drugs on the basisofcell survival following differential manipulation ofGSH levels in thesecell lines will bepresented.