Heterogeneity of glutathione content in human ovarian cancer

Intracellular glutathione (GSH) has been shown to be one of the major factors modulating tumor response to a variety of commonly used anti-neoplastic agents. In this study the GSH contents of human ovarian tumors from primary biopsies, nude mouse xenografts, and in vitro cell cultures were compared. Pronounced intratumor cell-to-cell heterogeneity in GSH content was observed in primary patient biopsies when assessed using flow cytometry. For example, in an ascites biopsy from a newly diagnosed patient, a 5.6-fold difference in GSH concentration existed between the cell subpopulations with the 5% highest and 5% lowest GSH contents. Similar intratumor heterogeneity in GSH content was also evident in nude mouse xenografts. In addition, for a particular tumor line, the intertumor variations of GSH content among individual whole tumors were much less than the intratumor variation among slices from an individual tumor. Nude mouse xenografts of human ovarian cancer had GSH contents that were on average only slightly lower (30%) than those found in primary biopsies. In contrast, tumor cells grown as in vitro cultures, particularly those in exponential growth phase, had GSH contents considerably greater (1.3- to 3.5-fold) than those found in situ. Plateau phase cultures, however, had lower GSH contents and were more comparable to those observed in tumors in vivo. Overall, it may be concluded that in situations where GSH plays an important part in determining tumor response to a particular treatment, nude mouse xenografts may represent the most appropriate experimental model system.