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This version published online on June 1, 2006
Endocrinology, doi:10.1210/en.2006-0414
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Submitted on March 30, 2006
Accepted on May 23, 2006

RETINOIC ACID AS A NOVEL MEDICAL THERAPY FOR CUSHING'S DISEASE IN DOGS

Victor Castillo, Damiana Giacomini, Marcelo Páez-Pereda, Johanna Stalla, Marta Labeur, Marily Theodoropoulou, Florian Holsboer, Ashley B. Grossman*, Günter K. Stalla, and Eduardo Arzt*

Unidad de Endocrinología. Hospital Escuela, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires, Argentina; Laboratorio de Fisiología y Biología Molecular, Dept. de Fisiología, Biología Molecular y Celular, FCEN, Universidad de Buenos Aires, Buenos Aires, Argentina; Max-Planck-Institute of Psychiatry, Kraepelinstrasse,10, 80804 Munich, Germany; and Department of Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1A 7BE, UK; Members of the IFYBINE-Argentine National Research Council (CONICET); Affectis Pharmaceuticals, Munich, Germany

* To whom correspondence should be addressed. E-mail: A.B.Grossman{at}qmul.ac.uk or earzt{at}fbmc.fcen.uba.ar.

Cushing’s disease is almost always due to a corticotrophin (ACTH)-secreting pituitary tumor, but effective medical therapy is currently limited. As retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing’s disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing’s disease was assigned for a period of 180 days. Clinical signs, plasma ACTH and {alpha}-MSH, the cortisol/creatinine urine ratio and pituitary MRI were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and {alpha}-MSH, and also in the RC/C ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity, and tumoral size, in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing’s disease.
Key words: Retinoic acid • Cushing's disease • ACTH • Dogs




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