Glutathione-S-transferase activity and isoenzyme levels measured by two methods in ovarian cancer, and their value as markers of disease outcome

Abstract

Summary A study has been carried out to investigate the cellular distribution and levels of glutathione-Stransferase isoenzymes (GST), acidic (7t), basic (x) and neutral (p), in ovarian tumour biopsies, and to measure GST activity in the same tumour specimens. Two methods of assessing isoenzyme levels (immunohistochemistry and Western blot) were compared. Well-known important clinicopathological features were correlated with response to treatment, overall survival and progression-free survival for each of 97 patients from whom biopsies had been obtained. The glutathione-S-transferase isoenzyme levels were also correlated with overall and progression-free survival, and with the important clinicopathological features. As expected, there was a significant correlation between FIGO stage, histological grade of tumour, amount of residual disease after staging laparotomy, response to chemotherapy, and both overall and progression-free survival. Glutathione-Stransferase isoenzyme levels (acidic, basic and neutral) measured by Western blot were not found to be significantly correlated with any of the clinicopathalogical parameters tested. Using the immunohistochemistry method of detection there was a correlation between the GST acidic isoenzyme level and the amount of residual disease remaining after initial debulking surgery (higher levels were detected in the group with no residual disease, P=0.034), and also between the GST acidic isoenzyme level and the type of chemotherapy regimen used. Higher levels of the acidic isoenzyme were present in tumour biopsies taken from the patient group who had received a combination regimen (cyclophosphamide, carboplatin, ifosfamide and doxorubicin). The neutral and basic GST isoenzyme levels were not significantly correlated with any of the clinicopathalogical parameters. None of the GST isoenzyme levels were significantly correlated with response to treatment, overall survival or progression-free survival (using either method of detection). Similarly, glutathione transferase activity showed no significant correlation with prognosis or survival.

Drug metabolism-related genes as potential biomarkers: analysis of expression in normal and tumour breast tissue

“…Early studies carried out in breast cancer patients failed to establish a correlation between GST expression and clinicopathological features such as disease-free and overall survival [34,35]. Confirming these results, no association was found between the expression of any of the GSTs analysed and response to treatment, overall survival and disease-free survival in ovarian cancer [36]. However, a more recent analysis found that patients homozygous for a GST A1 polymorphism that results in reduced expression of the enzyme showed a significant difference in 5-year survival after breast cancer treatment when compared to heterozygous patients [37]; indeed, low expression of GST A1 correlated with reduced risk of death in the 5 years following diagnosis.…”

GSTP1-1 in Ovarian Cyst Fluid and Disease Outcome of Patients With Ovarian Cancer

“…These conflicting results might be explained by differences in techniques used to quantify GSTP1-1 (Table 3). It has been shown that immunohistochemical quantification of GSTP1-1 did not always correlate with the concentrations of GSTP1-1 as measured in the tissue cells by other methods, such as Western blot analysis (9,14). Wrigley et al (14) concluded that the Western blotting technique was more sensitive than immunohistochemistry because it detected GSTP1-1 that had been missed by observer examination of stained sections.…”

“…It has been shown that immunohistochemical quantification of GSTP1-1 did not always correlate with the concentrations of GSTP1-1 as measured in the tissue cells by other methods, such as Western blot analysis (9,14). Wrigley et al (14) concluded that the Western blotting technique was more sensitive than immunohistochemistry because it detected GSTP1-1 that had been missed by observer examination of stained sections. In addition, different scoring systems to quantify GSTP1-1 by immunohistochemistry, observer variation in identifying positively stained cells, different cutoff points for discriminating high from low values, and different types of tissue, i.e., fresh versus formalin fixed and paraffin embedded may also be responsible for the conflicting findings.…”

“…In Table 3, we summarized published studies in which GSTP1-1 was determined in ovarian cancer tissue and related to the clinical outcomes of patients with EOC. Some researchers found a relationship between overexpression of GSTP1-1 in malignant ovarian tissue and poor prognosis or bad response to chemotherapy (8)(9)(10)(11)(12)(13), whereas others could not detect such an association (14)(15)(16)(17)(18)(19)(20)(21). These conflicting results might be explained by differences in techniques used to quantify GSTP1-1 (Table 3).…”

Comparison of clinical staging of benign and malignant ovarian tissues with DNA flow cytometry

“…Also, proliferative rate [9,12,15,[17][18][19][20][21][22][23][24] , growth factors and their receptors [25] , lamina receptors [26] and functional and structural alterations of oncogenes and oncosuppressor genes [21,22,[25][26][27][28][29] have been studied. Biomarkers directly involved in drug resistance, such as proteins associated with multidrug resistance detoxification [30][31][32][33][34][35][36] , have also been determined as indicators of clinical outcome. However, due to the marked biologic, pathologic, and clinical tumor heterogeneity, outcome and interpretation of translational studies are often not equivocal.…”