PubMed · 13777691
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J C TOUCHSTONE, W S BLAKEMORE. 1961. Urinary 6 beta-hydroxy-cortisol in adrenocortical hyperfunction.. https://doi.org/10.1210/jcem-21-3-263
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PURPOSE: Glucocorticoids such as dexamethasone are widely used for medication of urological diseases, e.g., as cotreatment of advanced prostate cancer, to improve appetite, weight loss, fatigue, relieve bone pain, diminish ureteric obstruction, to reduce the production of adrenal androgens, as an antiemetic in patients undergoing chemo- and/or radiotherapy together with serving as "standard" therapy arm in randomized studies. While the potent pro-apoptotic properties and the supportive effects of glucocorticoids to tumor therapy in lymphoid cells are well studied, the impact to growth of prostate and other urological carcinomas is unknown. METHODS: We isolated cells from surgical resections of 21 prostate tumors and measured apoptosis and viability in these primary cells and 17 established cell lines from human prostate, bladder, renal cell and testicular carcinomas. RESULTS: We found that dexamethasone induces resistance regarding exposure to several cytotoxic agents such as taxol, gemcitabine, cisplatin, 5-FU and gamma-irradiation in 86% of the freshly isolated prostate tumors and in 100% of the established urological cell lines. No difference in dexamethasone-mediated protection was found in normal, benign and malignant prostate tumors. CONCLUSIONS: These data show for the first time that dexamethasone induced therapy resistance in urological carcinomas is not the exception but a more common phenomenon and implicate that glucocorticoids may have two faces in cancer therapy, a beneficial and a dangerous one.
Corticosteroids are the most effective anti-inflammatory therapy for asthma and other chronic inflammatory and immune diseases. Recently new insights have been gained into the molecular mechanisms whereby corticosteroids suppress inflammation. Inflammation is characterised by the increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-kappaB and activator protein-1. These transcription factors bind to and activate coactivator molecules, which acetylate core histones and switch on gene transcription. Corticosteroids suppress the multiple inflammatory genes that are activated in asthmatic airways mainly by reversing histone acetylation of activated inflammatory genes through binding of glucocorticoid receptors to coactivators and recruitment of histone deacetylase-2 (HDAC2) to the activated inflammatory gene transcription complex. Activated glucocorticoid receptors also bind to recognition sites in the promoters of certain genes to activate their transcription, resulting in secretion of anti-inflammatory proteins, such as mitogen-activated protein kinase phosphatase, which inhibits MAP kinase signalling pathways. Glucocorticoid receptors may also interact with other recognition sites to inhibit transcription, for example of several genes linked to their side effects. In some patients with steroid-resistant asthma there are abnormalities in GR signalling pathways. In chronic obstructive pulmonary disease (COPD) patients and asthmatic patients who smoke HDAC2 is markedly impaired as a result of oxidative and nitrative stress so that inflammation is resistant to the anti-inflammatory effects of corticosteroids. Corticosteroids are likely to remain the mainstay of asthma therapy and new therapeutic strategies may reverse the corticosteroid insensitivity in COPD and severe asthma.
The diagnostic aspects of sporadic inclusion-body myositis (s-IBM), and a few comments on our own approach to its treatment, are presented to foster the goals of this symposium, which was organized to provoke new ideas concerning the cause and treatment of this currently unsolvable disease. s-IBM is the most common, progressive, debilitating muscle disease beginning in persons over age 50 years, and it is more common in men. Diagnostic parameters reviewed are clinical, muscle-biopsy histochemistry, electrophysiologic and CSF evaluations. Overall, the degenerative phenomena in s-IBM muscle fibers seem to be the major cause of the progressive, unstoppable weakness, rather than the lymphocytic inflammation. Available treatments are of only slight, temporary benefit for only some s-IBM patients, indicating a desperate need for definitive therapies.