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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Adenocarcinoma, Clear Cell, Adult, Aged, Aged, 80 and over, Apoptosis, Blotting, Western, Carcinoma, Papillary, Cystadenocarcinoma, Serous, Dexamethasone, Dual Specificity Phosphatase 1, Female, Glucocorticoids, Humans, Immediate-Early Proteins, Middle Aged, Ovarian Neoplasms, Placebos, Protein-Serine-Threonine Kinases, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured.
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Is administration of glucocorticoids to ovarian cancer patients associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues? Context: To prevent chemotherapy-related side effects, synthetic glucocorticoids, for example, dexamethasone, are routinely administered to patients with ovarian cancer. However, preclinical data implicate glucocorticoids in suppressing chemotherapy-mediated apoptosis in epithelial tumors. The anti-apoptotic mechanisms underlying this increased survival have been shown to require up-regulation of prosurvival genes, including serum and glucocorticoid-regulated kinase 1 (SGK1) and map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Despite abundant preclinical data, there are no correlative studies in patients. We therefore evaluated anti-apoptotic gene expression in tumor samples from patients randomized to dexamethasone or normal saline. Eighteen patients were randomized before exploratory laparotomy for suspected ovarian cancer. Dexamethasone or normal saline was administered i.v. following anesthesia. Ovarian and omental tumor samples were collected intra-operatively before and after infusion. Samples were analyzed for histology and glucocorticoid receptor expression by immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were determined using quantitative real-time PCR. Ten patients were evaluable. At 30 min postinfusion, tumor samples from five patients receiving dexamethasone revealed an average SGK1 mRNA induction of 6.1-fold (SEM, +/-2.6) compared with only 1.5-fold (SEM, +/-0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, +/-2.9) following dexamethasone versus 1.1-fold (SEM, +/-0.4) following normal saline (P = 0.009). All samples expressed glucocorticoid receptor.
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Glucocorticoid administration to patients is associated with rapid up-regulation of SGK1 and MKP1 expression in ovarian tumors. This finding supports the hypothesis that pharmacologic doses of glucocorticoids may decrease chemotherapy effectiveness in ovarian cancer patients through increased anti-apoptotic gene expression. Final Decision: yes