Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ketoconazole is a well-tolerated, synthetic, imidazole derivative currently in widespread therapeutic use against mycotic infections. Recent evidence that it depresses testosterone synthesis in humans prompted us to investigate the effects in rats of its administration alone or in combination with the gonadotropin releasing hormone superagonist analogue leuprolide. Plasma luteinizing hormone, testosterone, and ketoconazole levels as well as ventral prostate weight and tumor growth in rats bearing the androgen-dependent Dunning R3327H model of prostate adenocarcinoma were measured. Doses of 30 mg/kg twice daily of ketoconazole alone depressed plasma testosterone levels by approximately 75% to a nadir of 0.47 +/- 0.08 (SE) ng/ml on day 20 (P less than 0.001 versus basal). This effect of ketoconazole was exerted directly at the testicular level since plasma luteinizing hormone levels were not suppressed. In response, ventral prostate weight declined and growth of the Dunning R3327H tumor was retarded to rates observed in castrate controls. Leuprolide alone lowered basal testosterone levels to 0.20 +/- 0.02 ng/ml after 35 days of daily administration but persistent androgen increments after each injection (acute-on-chronic effect) were observed (i.e., to 4.41 +/- 0.62 ng/ml). The addition of ketoconazole to leuprolide inhibited the acute-on-chronic rise in testosterone to 0.33 +/- .07 ng/ml and also lowered basal testosterone levels further to 0.11 +/- 0.01 on day 10 of combined administration. Ketoconazole also blunted the response to the first injection of leuprolide from a 3-h peak level of 8.74 +/- 0.53 to 4.17 +/- 0.80 with the 40 mg/kg dose. These results indicate that combining ketoconazole with leuprolide achieves greater suppression of testosterone than either agent alone. When such protocols are applied to humans with prostate cancer, more extensive effects may be expected because of the greater sensitivity of patients than of the rodent species to these agents.
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PMID:Inhibition of testosterone production with ketoconazole alone and in combination with a gonadotropin releasing hormone analogue in the rat. 307 88

Cushing's disease caused by a microadenoma located near the pituitary stalk is infrequent and spontaneous remission caused by necrosis of a corticotropinoma in such location has not been reported. A 42-year-old woman with ACTH-dependent Cushing's syndrome presented on magnetic resonance imaging (MRI) a 3-mm microadenoma attached to the pituitary stalk. Treatment with ketoconazole normalized urinary free cortisol (UFC) from 433.0 to 66.0 microg/day, although it failed to reduce elevated serum androgen levels (DHEAS 4770 ng/ml). After one year, treatment was stopped and UFC rose again to 936.0 microg/day but one month later the patient presented acute headache and signs of steroid withdrawal syndrome. Endocrine evaluation showed glucocorticoid and androgen deficiency (UFC 5.0 microg/day; DHEAS < 300 ng/ml); control MRI revealed disappearance of the microadenoma. Cushingoid signs subsided and steroid replacement was initiated, proving still necessary over two years after the episode. Infarction or hemorrhage of a corticotrope adenoma could be a probable underlying mechanism although its precipitating factor is unclear. Ketoconazole withdrawal, through abrupt increase in cortisol production and/or the interruption of a hypothetical inhibitory action on cell replication followed by tumor growth and compromise of vascular supply, may be considered as possible triggering factors. To the best of our knowledge, this is the first report of spontaneous remission of Cushing's disease caused by presumed infarction of a microadenoma, unusually located in the superior rim of the pituitary, attached to the stalk.
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PMID:Spontaneous remission of Cushing's disease after disappearance of a microadenoma attached to the pituitary stalk. 1563 98

OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD. METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase "(name of agent) and Cushing's" was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review. RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%-100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth. CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.
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PMID:Cushing's disease: current medical therapies and molecular insights guiding future therapies. 2563 13