Potential for selective modulation of glutathione in cancer chemotherapy.

Notwithstanding ongoing progress in anticancer therapeutics development, the persistent problem remains to selectively target tumors while sparing normal tissues. This is confounding largely because the differences between normal and tumor cells are often subtle and part of a gradient, where a gene product may be more or less expressed in tumor compared with the host normal tissue, but seldom expressed (or turned off) in tumors. The role of glutathione (GSH) and related enzymes in cellular resistance to xenobiotics, including chemotherapy is well established. This study is among those attempting to modulate GSH to therapeutic advantage. The authors briefly describe the experience with the gamma-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-carboxylate. 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 drug toxicity. Using high affinity antibodies the authors have generated interesting information on the distribution of this enzyme in tumor versus normal human tissues. Finally, the authors have been studying the potential for modulating gap junctions as a part of anti-cancer therapeutics, since they transport GSH between cells and are generally deficient in tumor cells. Preliminary studies suggest that gap junction induction may dramatically deplete GSH concentration in tumor cells and sensitize them to a variety of treatments.