PMC:3724972 / 21319-25902 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3724972","sourcedb":"PMC","sourceid":"3724972","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3724972","text":"Other investigational therapies\n\nCombination somatostatin analog-dopamine agonist\nCombined use of a somatostatin analog and a dopamine agonist for treatment of CD has been proposed on the basis of similar studies suggesting additive effects on growth hormone secretion from somatotroph adenomas [60]. In a study of 17 patients with CD, pasireotide monotherapy (100–250 mcg three times a day) normalized UFC levels in 5 patients, and addition of cabergoline (0.5–1.5 mg every other day) normalized UFC levels in 4 more patients. Among the remaining 8 patients, subsequent addition of ketoconazole (200 mg three times a day) normalized UFC levels in 6, leaving only 2 patients who still had elevated UFC levels. Thus, sequential therapy using these three agents shows promise but requires further studies of both efficacy and safety [61].\n\nTemozolomide monotherapy and in combination\nTemozolomide, an oral alkylating agent typically used in chemotherapeutic treatment of astrocytoma and melanoma, has shown promise as monotherapy [62, 63], and in combination with pasireotide [64], as a treatment for aggressive pituitary adenomas and carcinomas.\nTo date, ~30 cases of pituitary adenoma have been treated with temozolomide (including ten ACTH-secreting adenomas). Overall reported response rate is approximately 60 % [62, 63]; however, information on temozolomide treatment of pituitary adenomas is currently confined to individual case reports and three case series [65–67]. An inverse relationship between tumoral O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression and response to temozolomide therapy has been suggested, but not confirmed in all studies [62, 65, 67, 68].\nTemozolomide may represent a viable treatment option for aggressive corticotroph adenomas refractory to surgery, radiotherapy, or other medical treatment. In tumors that responded to temozolomide, the clinical response was associated with prompt reductions in ACTH, chiasmatic compression and mass effects. Thus, it is possible to evaluate response early in the course of treatment. Targeted modulation of MGMT expression may be useful in patients who may otherwise not respond to temozolomide therapy [63].\n\nRetinoic acid\nThe retinoic acid receptor is a type II nuclear receptor involved with transcriptional regulation. In a murine corticotrope tumor cell line, retinoic acid has been shown to reduce ACTH secretion and pro-opiomelanocortin (POMC) synthesis. Further, there is evidence that, with prolonged treatment, retinoic acid induces increased caspase-3 activity and cell death in ACTH-secreting cells. It has also demonstrated inhibition of corticosterone production and cell proliferation in adrenal cortex cells [69]. Retinoic acid had demonstrated reduced ACTH secretion and prevented tumor growth in mice with implanted with tumoral corticotropes [70]. In a 6-month study in dogs with spontaneous corticotrope tumors, retinoic acid reduced cortisol excess and improved associated symptoms [71].\nA recent small study showed a marked reduction in UFC levels in 5/7 patients (22–73 % of baseline values), and UFC normalization in three patients. There was no apparent pattern of decrease in plasma cortisol. Plasma ACTH decreased in the first month of treatment and then returned to pretreatment levels in responsive patients. Blood pressure, glycemia, and signs of hypercortisolism improved on treatment. Patients reported only mild adverse effects (e.g., xerophthalmia and arthralgias) [59].\n\nEGFR\nThe epidermal growth factor receptor (EGFR) family has recently been studied as a therapeutic target for CD. In cultured human and canine corticotroph tumors, gefitinib (an EGFR tyrosine kinase inhibitor) attenuated POMC expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. In murine studies, gefitinib decreased tumor size and corticosterone levels, and reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat [72]. These results indicate that inhibiting EGFR signaling may be a valuable strategy for treating CD. Further studies evaluating clinical efficacy and safety in patients with CD are needed.\n\nDoxazosin\nThe selective alpha(1)-adrenergic receptor antagonist, doxazosin has been shown to decrease plasma ACTH and inhibit proliferation in human and murine pituitary tumor cells, and may represent a potentially useful treatment option in pituitary adenomas [73]. However, there is currently no clinical experience with doxazosin, and more data are required before any such treatment strategy could be advocated.","divisions":[{"label":"title","span":{"begin":0,"end":31}},{"label":"sec","span":{"begin":33,"end":836}},{"label":"title","span":{"begin":33,"end":81}},{"label":"p","span":{"begin":82,"end":836}},{"label":"sec","span":{"begin":838,"end":2192}},{"label":"title","span":{"begin":838,"end":881}},{"label":"p","span":{"begin":882,"end":1144}},{"label":"p","span":{"begin":1145,"end":1684}},{"label":"p","span":{"begin":1685,"end":2192}},{"label":"sec","span":{"begin":2194,"end":3488}},{"label":"title","span":{"begin":2194,"end":2207}},{"label":"p","span":{"begin":2208,"end":2992}},{"label":"p","span":{"begin":2993,"end":3488}},{"label":"sec","span":{"begin":3490,"end":4166}},{"label":"title","span":{"begin":3490,"end":3494}},{"label":"p","span":{"begin":3495,"end":4166}},{"label":"title","span":{"begin":4168,"end":4177}}],"tracks":[{"project":"2_test","denotations":[{"id":"23673515-17413190-63233656","span":{"begin":296,"end":298},"obj":"17413190"},{"id":"23673515-20463350-63233657","span":{"begin":832,"end":834},"obj":"20463350"},{"id":"23673515-20972839-63233658","span":{"begin":1029,"end":1031},"obj":"20972839"},{"id":"23673515-22584716-63233659","span":{"begin":1033,"end":1035},"obj":"22584716"},{"id":"23673515-20496311-63233660","span":{"begin":1075,"end":1077},"obj":"20496311"},{"id":"23673515-20972839-63233661","span":{"begin":1316,"end":1318},"obj":"20972839"},{"id":"23673515-22584716-63233662","span":{"begin":1320,"end":1322},"obj":"22584716"},{"id":"23673515-20668043-63233663","span":{"begin":1466,"end":1468},"obj":"20668043"},{"id":"23673515-20870708-63233663","span":{"begin":1466,"end":1468},"obj":"20870708"},{"id":"23673515-20660056-63233663","span":{"begin":1466,"end":1468},"obj":"20660056"},{"id":"23673515-20972839-63233664","span":{"begin":1668,"end":1670},"obj":"20972839"},{"id":"23673515-20668043-63233665","span":{"begin":1672,"end":1674},"obj":"20668043"},{"id":"23673515-20660056-63233666","span":{"begin":1676,"end":1678},"obj":"20660056"},{"id":"23673515-17926052-63233667","span":{"begin":1680,"end":1682},"obj":"17926052"},{"id":"23673515-22584716-63233668","span":{"begin":2188,"end":2190},"obj":"22584716"},{"id":"23673515-11602619-63233669","span":{"begin":2709,"end":2711},"obj":"11602619"},{"id":"23673515-16195406-63233670","span":{"begin":2846,"end":2848},"obj":"16195406"},{"id":"23673515-16740975-63233671","span":{"begin":2988,"end":2990},"obj":"16740975"},{"id":"23673515-22851491-63233672","span":{"begin":3484,"end":3486},"obj":"22851491"},{"id":"23673515-22105169-63233673","span":{"begin":3976,"end":3978},"obj":"22105169"},{"id":"23673515-16020484-63233674","span":{"begin":4430,"end":4432},"obj":"16020484"}],"attributes":[{"subj":"23673515-17413190-63233656","pred":"source","obj":"2_test"},{"subj":"23673515-20463350-63233657","pred":"source","obj":"2_test"},{"subj":"23673515-20972839-63233658","pred":"source","obj":"2_test"},{"subj":"23673515-22584716-63233659","pred":"source","obj":"2_test"},{"subj":"23673515-20496311-63233660","pred":"source","obj":"2_test"},{"subj":"23673515-20972839-63233661","pred":"source","obj":"2_test"},{"subj":"23673515-22584716-63233662","pred":"source","obj":"2_test"},{"subj":"23673515-20668043-63233663","pred":"source","obj":"2_test"},{"subj":"23673515-20870708-63233663","pred":"source","obj":"2_test"},{"subj":"23673515-20660056-63233663","pred":"source","obj":"2_test"},{"subj":"23673515-20972839-63233664","pred":"source","obj":"2_test"},{"subj":"23673515-20668043-63233665","pred":"source","obj":"2_test"},{"subj":"23673515-20660056-63233666","pred":"source","obj":"2_test"},{"subj":"23673515-17926052-63233667","pred":"source","obj":"2_test"},{"subj":"23673515-22584716-63233668","pred":"source","obj":"2_test"},{"subj":"23673515-11602619-63233669","pred":"source","obj":"2_test"},{"subj":"23673515-16195406-63233670","pred":"source","obj":"2_test"},{"subj":"23673515-16740975-63233671","pred":"source","obj":"2_test"},{"subj":"23673515-22851491-63233672","pred":"source","obj":"2_test"},{"subj":"23673515-22105169-63233673","pred":"source","obj":"2_test"},{"subj":"23673515-16020484-63233674","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ec93c7","default":true}]}]}}