MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas.

Walls, Gerard V; Lemos, Manuel C; Javid, Mahsa; Bazan-Peregrino, Miriam; Jeyabalan, Jeshmi; Reed, Anita A C; Harding, Brian; Tyler, Damian J; Stuckey, Daniel J; Piret, Sian; Christie, Paul T; Ansorge, Olaf; Clarke, Kieran; Seymour, Len; Thakker, Rajesh V

Walls, Gerard V; Lemos, Manuel C; Javid, Mahsa; Bazan-Peregrino, Miriam; Jeyabalan, Jeshmi; Reed, Anita A C; Harding, Brian; Tyler, Damian J; Stuckey, Daniel J; Piret, Sian; Christie, Paul T; Ansorge, Olaf; Clarke, Kieran; Seymour, Len; Thakker, Rajesh V.

Afiliación

Walls GV; Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom.

Cancer Res ; 72(19): 5060-8, 2012 Oct 01.

Article en En | MEDLINE | ID: mdl-22915754

RESUMEN

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combined occurrence of pituitary, pancreatic, and parathyroid tumors showing loss of heterozygosity in the putative tumor suppressor gene MEN1. This gene encodes the protein menin, the overexpression of which inhibits cell proliferation in vitro. In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1(+/-) mice, using a recombinant nonreplicating adenoviral serotype 5 vector that contained the murine Men1 cDNA under control of a cytomegalovirus promoter (Men1.rAd5). Pituitary tumors in 55 Men1(+/-) female mice received a transauricular intratumoral injection of Men1.rAd5 or control treatments, followed by 5-bromo-2-deoxyuridine (BrdUrd) in drinking water for four weeks before magnetic resonance imaging (MRI) and immunohistochemical analysis. Immediate procedure-related and 4-week mortalities were similar in all groups, indicating that the adenoviral gene therapy was not associated with a higher mortality. Menin expression was higher in the Men1.rAd5-treated mice when compared with other groups. Daily proliferation rates assessed by BrdUrd incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control-treated tumors. In contrast, apoptotic rates, immune T-cell response, and tumor volumes remained similar in all groups. Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation.

Asunto(s)

Adenoma/terapia; Proliferación Celular; Modelos Animales de Enfermedad; Terapia Genética/métodos; Neoplasias Hipofisarias/terapia; Proteínas Proto-Oncogénicas/genética; Adenoma/genética; Adenoma/metabolismo; Adenoviridae/genética; Animales; Vectores Genéticos/genética; Células HEK293; Humanos; Inmunohistoquímica; Imagen por Resonancia Magnética; Ratones; Ratones de la Cepa 129; Ratones Endogámicos C57BL; Ratones Noqueados; Hipófisis/diagnóstico por imagen; Hipófisis/metabolismo; Hipófisis/patología; Neoplasias Hipofisarias/genética; Neoplasias Hipofisarias/metabolismo; Proteínas Proto-Oncogénicas/metabolismo; Radiografía

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Hipofisarias / Terapia Genética / Adenoma / Proteínas Proto-Oncogénicas / Proliferación Celular / Modelos Animales de Enfermedad Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2012 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos

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