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.