Abstract
There is evidence to suggest that glutathione (GSH) and glutathione-S-transferases (GST) are important factors in determining sensitivity to cytotoxic drugs in vitro and in preclinical in vivo model systems. To define the relationship between tumour GSH concentration, GST isoenzyme expression and response to carboplatin in epithelial ovarian cancer (EOC), tumour samples from 39 patients with assessable disease after primary surgery were analyzed for GSH content and GST expression. Response was assessed after completing six courses of single agent carboplatin therapy. GSH was measured by high performance liquid chromatography (HPLC) in fresh tumour samples taken at primary laparatomy. GST isoenzyme expression was assessed by immunohistochemistry of fixed tumour material using antibodies specific for pi, alpha and mu classes. GST isoenzyme expression was defined as positive if the staining intensity was strong and more than 10% of tumour cells were involved. The mean GSH concentrations were: 8351 +/- 4496, 7211 +/- 5026, 6559 +/- 4573 and 3758 +/- 1885 (nmol g-1 tissue dry weight mean +/- s.d.) for tumours from patients who subsequently achieved a complete response (CR, n = 18), partial response (PR, n = 10) or who had static disease (SD, n = 7) or progressive disease (PD, n = 4) respectively. There was no relationship between GSH concentration and response (ANOVA, P = 0.32). There were also no relationship between GST isoenzyme expression and response (P Fisher's exact test 0.51-0.55 and chi-squared test 0.98-0.99). In conclusion, there was no association between the concentration of GSH or expression of GST isoenzymes and response to single agent carboplatin in primary previously untreated EOC.
Highlights
For the purpose of this study, and in analysing the results in relation to response, patients were divided into two groups: responders and non-responders; glutathione S-transferases (GSTs) isoenzyme expression was defined as positive if the staining intensity was strong and more than 10% of the tumour cells stained positive
From the results presented it is clear that, in this clinical setting, there was no marked relationship between GSH concentrations in primary epithelial ovarian cancer (EOC) tumour samples and subsequent response to carboplatin chemotherapy
Platinum compounds are among the most effective agents for the treatment of patients with EOC and carboplatin has been used as a single agent in the Northern Region (UK) for expression of GSTs with resistance to cytotoxic drugs in a variety of tumours including colorectal (Mulder et al, 1995) and lung cancer (Inoue et al, 1995), in which expression of the it isoform was implicated, and acute lymphoblastic leukaemia (Hall et al, 1994b) in which expression of, class GST was associated with an increased probability of relapse
Summary
The aim of this study was to relate response to single-agent carboplatin to tumour levels of GSH and GST in EOC
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