POTENTIAL FOR SELECTIVE MODULATION OF GLUTATHIONE IN CANCER-CHEMOTHERAPY

Notwithstanding ongoing progress in anticancer therapeutics developmen t, the persistent problem remains to selectively target tumors while s paring normal tissues. This is confounding largely because the differe nces between normal and tumor cells are often subtle and part of a gra dient, where a gene product may be more or less expressed in tumor com pared with the host normal tissue, but seldom expressed (or turned off ) in tumors. The role of glutathione (GSH) and related enzymes in cell ular resistance to xenobiotics, including chemotherapy is well establi shed. This study is among those attempting to modulate GSH to therapeu tic advantage. The authors briefly describe the experience with the ga mma-glutamylcysteine synthetase inhibitor buthionine sulfoximine, and then in greater detail outline recent evidence for a potentially more selective approach using the cysteine prodrug L-2-oxothiazolidine-4-ca rboxylate . This has led to a detailed study of the activating enzyme 5-oxo-L-prolinase, including enzymatic and immunocharacterization, as well as in vitro study of the effect of its modulators on anticancer d rug toxicity. Using high affinity antibodies the authors have generate d interesting information on the distribution of this enzyme in tumor versus normal human tissues. Finally, the authors have been studying t he potential for modulating gap junctions as a part of anti-cancer the rapeutics, since they transport GSH between cells and are generally de ficient in tumor cells. Preliminary studies suggest that gap junction induction may dramatically deplete GSH concentration in tumor cells an d sensitize them to a variety of treatments. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.