Potential for selective modulation of glutathione in cancer chemotherapy1

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Abstract

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 γ-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.

Introduction

The concept of selective glutathione (GSH) modulation cited in this report refers to the strategy of the preferential modulation of GSH in normal or tumor cells. The feasibility of such selectivity depends on the physiological difference between normal and tumor cells, which upon exposure to a selective GSH modulator, leads to the different responses in the two types of cells. In this chapter the authors report the preliminary studies of three targets under the investigation for selective GSH modulation: γ-glutamylcysteine synthetase (γ-GCS), 5-oxo-l-prolinase (5-OPase) and gap junction intercellular communication (GJIC).

Section snippets

GSH modulation

GSH (l-glutamyl-l-cysteinyl-glycine) is a tripeptide thiol found in virtually all cells. Biosynthesis and metabolism of GSH is carried out via the function of the γ-glutamyl cycle which is composed of a series of inter-related enzymatic reactions [1](Fig. 1). The de novo synthesis pathway of GSH includes two sequential, ATP-dependent enzymatic steps from the constituent amino acids glutamate (GLU), cysteine and glycine via the function of γ-GCS, the rate limiting step which forms an amide

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    Presented at the International Conference on Glutathione and Glutathione-Linked Enzymes in Human Cancer and Other Diseases, Hilton Head, SC, USA, November 1996.

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