PURPOSE: 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. EXPERIMENTAL DESIGN: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. RESULTS: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. CONCLUSION: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.
RCT Entities:
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: 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 cancerpatients through increased anti-apoptotic gene expression.
Authors: E D Weitzman; D Fukushima; C Nogeire; H Roffwarg; T F Gallagher; L Hellman Journal: J Clin Endocrinol Metab Date: 1971-07 Impact factor: 5.958
Authors: Carsten Denkert; Wolfgang D Schmitt; Stefan Berger; Angela Reles; Sören Pest; Antje Siegert; Werner Lichtenegger; Manfred Dietel; Steffen Hauptmann Journal: Int J Cancer Date: 2002-12-10 Impact factor: 7.396
Authors: Amal Melhem-Bertrandt; Mariana Chavez-Macgregor; Xiudong Lei; Erika N Brown; Richard T Lee; Funda Meric-Bernstam; Anil K Sood; Suzanne D Conzen; Gabriel N Hortobagyi; Ana-Maria Gonzalez-Angulo Journal: J Clin Oncol Date: 2011-05-31 Impact factor: 44.544
Authors: Maxwell N Skor; Erin L Wonder; Masha Kocherginsky; Anju Goyal; Ben A Hall; Yi Cai; Suzanne D Conzen Journal: Clin Cancer Res Date: 2013-09-09 Impact factor: 12.531
Authors: Abena S Agyeman; Wesley J Jun; David A Proia; Caroline R Kim; Maxwell N Skor; Masha Kocherginsky; Suzanne D Conzen Journal: Horm Cancer Date: 2016-02-08 Impact factor: 3.869
Authors: Erica M Stringer-Reasor; Gabrielle M Baker; Maxwell N Skor; Masha Kocherginsky; Ernst Lengyel; Gini F Fleming; Suzanne D Conzen Journal: Gynecol Oncol Date: 2015-06-24 Impact factor: 5.482
Authors: Jennifer Taylor Veneris; Kathleen M Darcy; Paulette Mhawech-Fauceglia; Chunqiao Tian; Ernst Lengyel; Ricardo R Lastra; Tanja Pejovic; Suzanne D Conzen; Gini F Fleming Journal: Gynecol Oncol Date: 2017-04-26 Impact factor: 5.482