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Adenovirus-Mediated Targeted Expression of Toxic Genes to Adrenocorticotropin-Producing Pituitary Tumors Using the Proopiomelanocortin Promoter

 Eun Jig Lee  ;  Fred Martinson  ;  Tom Kotlar  ;  Bayar Thimmapaya  ;  J. Larry Jameson 
 Journal of Clinical Endocrinology & Metabolism, Vol.86(7) : 3400-3409, 2001 
Journal Title
 Journal of Clinical Endocrinology & Metabolism 
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Management of Cushing’s disease remains challenging, despite advances in its diagnosis and treatment. Here, we describe a strategy for targeting the expression of toxic genes to ACTH-producing tumor cells using adenoviral vectors. The POMC promoter was used to express either a marker gene (β-galactosidase) or a toxic gene [herpes simplex virus thymidine kinase (TK)]. In ACTH-producing AtT20 cells, infection with recombinant adenoviruses containing the POMC promoter (AdPOMCGal; AdPOMCTK) led to high-level gene expression. Stereotactic injection of AdPOMCGal into the rat pituitary resulted in localized expression of the β-galactosidase transgene in corticotrope cells. Cytotoxicity studies were performed using the TK-containing vectors and treatment with ganciclovir. AdPOMCTK caused greater than 95% cytotoxicity of AtT20 cells at a viral dose (multiplicity of infection, 5 plaque-forming units/cell) that induced minimal toxicity using control viruses. No cellular toxicity was seen using a nonpituitary cell line (T47D breast tumor cells). AtT20 cells transplanted into nude mice induced features of Cushing’s syndrome and were used as an in vivo model of ACTH-producing tumors. Injection of the AdPOMCTK virus caused significant regression of the transplanted AtT20 tumors. These studies suggest that the POMC promoter may provide a useful gene therapy strategy for the adjunctive treatment of pituitary tumors causing ACTH-dependent Cushing’s syndrome.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
Yonsei Authors
이은직(Lee, Eun Jig) ORCID logo https://orcid.org/0000-0002-9876-8370
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