Effect of protracted treatment with rosiglitazone, a PPARγ agonist, in patients with Cushing's disease

Giraldi, Francesca Pecori; Scaroni, Carla; Arvat, Emanuela; Martin, Martina De; Giordano, Roberta; Albiger, Nora; Leão, Adriana Antonio Silva; Picu, Andreea; Mantero, Franco; Cavagnini, Francesco

doi:10.1111/j.1365-2265.2006.02452.x

Cited by 80 publications

(47 citation statements)

References 19 publications

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“…Concerns about the potential cardiovascular risks (Nissen & Wolski 2007) of using RGZ at doses higher than 8 mg/day should be inconsistent since, at variance with diabetic subjects, ACC patients seldom suffer from cardiovascular or renal complications. Moreover, an overall well-tolerated RGZ administration was reported in patients with Cushing's disease (Pecori Giraldi et al 2006) or solid tumors (Read et al 2008) at doses (12 and 16 mg/die for up to 8 months) higher than those used in diabetes treatment. Of note, we obtained a 70% inhibition of xenograft tumor growth with a RGZ dose 30 time lower than those currently used in xenograft studies (Heaney et al 2002), without observing body weight loss or toxicity during the treatment.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Luconi¹,

Mangoni²,

Gelmini³

et al. 2010

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare aggressive tumor with a poor prognosis. The lack of a specific and effective medical treatment is due to the poor knowledge of the mechanisms underlying tumor growth. Research on potential drugs able to specifically interfere with tumor proliferation is essential to develop more efficacious therapies. We evaluated for the first time the in vivo effect of rosiglitazone (RGZ), an anti-diabetic drug with in vitro anti-tumor properties, on ACC proliferation in a xenograft model obtained by s.c. injection of human ACC H295R cells in athymic mice. When the tumor size reached 5 mm, animals were allocated to 5 mg/kg RGZ-or water-treated groups. Tumor volume was measured twice a week. A significant reduction of tumor growth in RGZ versus control (control) group was observed and was already maximal following 17 day treatment (1KT/CZ75.4% (43.7-93.8%)). After 31 days of treatment, mice were killed and tumor analyzed. Tumor histological evaluation revealed characteristics of invasiveness, richness in small vessels and mitotic figures in control group, while RGZ group tumors presented non infiltrating borders, few vessels, and many apoptotic bodies. Tumor immunohistochemistry showed that Ki-67 was reduced in RGZ versus control group. Quantitative real-time RT-PCR demonstrated a significant reduction in the expression of angiogenic (VEGF), vascular (CD31), proliferation (BMI-1), and anti-apoptotic (Bcl-2) genes in RGZ versus control group tumors. The same inhibitory effects were confirmed in in vitro RGZ-treated H295R. Our findings support and expand the role of RGZ in controlling ACC proliferation and angiogenesis in vivo and in vitro.

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Section: Discussionmentioning

confidence: 99%

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Luconi¹,

Mangoni²,

Gelmini³

et al. 2010

Endocrine-Related Cancer

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“…Current therapeutic strategies include pituitary surgery and radiation, adrenalectomy, and medical treatment with steroidogenesis inhibitors, because drugs aimed at the pituitary adenoma have proven effective in only a percentage of patients (1,2). In fact, dopamine and peroxisome proliferator-activated receptor ␥ (PPAR␥) as well as somatostatin receptor agonists resulted in normalization of cortisol excess and amelioration of symptoms in some 30% of patients (3)(4)(5).…”

mentioning

confidence: 99%

Potential Role for Retinoic Acid in Patients with Cushing's Disease

Giraldi

Ambrogio

Andrioli³

et al. 2012

The Journal of Clinical Endocrinology & Metabolism

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104

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Context: Cushing's disease, i.e. cortisol excess due to an ACTH-secreting pituitary adenoma, is a rare disorder with considerable morbidity and mortality but no satisfactory medical treatment as yet. Experimental data have recently shown that retinoic acid restrains ACTH secretion by tumoral corticotropes.Objective: Our objective was to evaluate the efficacy and safety profile of retinoic acid treatment in patients with Cushing's disease.Design: This is a prospective, multicenter study. Seven patients with Cushing's disease (three men, four postmenopausal women) were started on 10 mg retinoic acid daily and dosage increased up to 80 mg daily for 6 -12 months. ACTH, urinary free cortisol (UFC), and serum cortisol as well as clinical features of hypercortisolism and possible side effects of retinoic acid were evaluated at baseline, during retinoic acid administration, and after drug withdrawal.Results: A marked decrease in UFC levels was observed in five patients; mean UFC levels on retinoic acid were 22-73% of baseline values and normalization in UFC was achieved in three patients. Plasma ACTH decreased in the first month of treatment and then returned to pretreatment levels in responsive patients whereas no clear-cut pattern could be detected for serum cortisol. Blood pressure, glycemia, and signs of hypercortisolism, e.g. body weight and facial plethora, were ameliorated to a variable extent on treatment. Patients reported only mild adverse effects, e.g. xerophthalmia and arthralgias. Abbreviations: COUP-TF1, Chicken ovoalbumin upstream promoter transcription factor 1; PPAR␥, peroxisome proliferator-activated receptor ␥; UFC, urinary free cortisol; WBC, white blood cells.

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“…In a second study of ten patients, four prior to surgery, four following relapse after surgery and two immediately after failed surgery treated with 4-16 mg of rosiglitazone for 1-8 months (median 3 months), there was no consistent reduction in urinary free cortisol, plasma ACTH or serum cortisol levels (60). Side effects reported included oedema, weight increase, somnolence and increased hirsutism.…”

Section: Ppar-γ Receptor Agonistsmentioning

confidence: 99%

Pharmacological management of Cushing's syndrome: an update

Dang

Trainer

2007

Arq Bras Endocrinol Metab

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The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. RESUMOManejo Farmacológico da Síndrome de Cushing: Uma Atualização. O tratamento de escolha para a síndrome de Cushing ainda é a cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para controlar o hipercortisolismo antes da cirurgia e otimizar o estado pré-operatório do paciente e, adicionalmente, quando ocorre falha cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais medicamentos são empregados para inibir a esteroidogênese e incluem: metirapona, cetoconazol e mitotano. Medicamentos visando o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel na prática clínica permanece limitado, embora o agonista PPAR-γ e análogo de somatostatina, som-230 (pasireotídeo), requeira estudos adicionais. A única droga que age perifericamente no receptor glicocorticóide é a mifepristona (RU486). O manejo da síndrome de Cushing deve envolver uma combinação terapêutica atuando em diferentes vias da hipercortisolemia, mas o monitoramento dessa terapia ainda permanece um desafio. (Arq Bras Endocrinol Metab

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Effect of protracted treatment with rosiglitazone, a PPARγ agonist, in patients with Cushing's disease

Cited by 80 publications

References 19 publications

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Potential Role for Retinoic Acid in Patients with Cushing's Disease

Pharmacological management of Cushing's syndrome: an update

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