title: Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppresses growth of estrogen-induced pituitary prolactinomas.
abstract: Prolactin-secreting adenomas are one of the most common types of intracranial neoplasm found in humans. The modalities of clinical treatment currently in use include D(2)-dopamine receptor agonists, surgery, and radiotherapy, and the success rates for treatment are good. However, there are prolactinomas that are difficult to treat. As an alternative, we have developed a gene therapy strategy in which the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), is overexpressed in the anterior pituitary (AP) gland. Because dopamine is known to have an inhibitory effect on lactotroph growth and prolactin secretion, we developed a system that would enable its local synthesis from freely available precursor amino acids. A dual adenovirus tetracycline-regulatable expression system was generated to control the production of TH. In the absence but not presence of the tetracycline analog doxycycline, TH expression was observed in AP tumor cell lines AtT20, GH3, and MMQ. In both primary AP cell cultures and the AP gland, in situ expression of TH was seen in lactotrophs, somatotrophs, corticotrophs, thyrotrophs, and gonadotrophs in the absence but not presence of doxycycline. The ability of this system to inhibit hyperprolactinemia and pituitary lactotroph hyperplasia was then assessed in a model of estrogen- or estrogen/sulpiride-induced pituitary tumors. In the absence but not presence of doxycycline, a 49% reduction in pituitary growth and 58% reduction in the increase of circulating prolactin levels were observed in estrogen, but not estrogen/sulpiride, treated rats. These results indicate that in situ dopamine enhancement gene therapy can be a useful tool for the treatment of prolactinoma. Dopamine synthesis can be tightly regulated and the therapeutic benefit of the system is only inhibited when local dopamine signaling is impaired.
authors.affiliation: Molecular Medicine and Gene Therapy Unit, School of Medicine, University of Manchester, Room 1.302, Stopford Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Williams
authors.forename: D
authors.initials: D
authors.lastname: Stone
authors.forename: J R
authors.initials: JR
authors.lastname: Smith-Arica
authors.forename: I D
authors.initials: ID
authors.lastname: Morris
authors.forename: P R
authors.initials: PR
authors.lastname: Lowenstein
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004967:Estrogens; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D010911:Pituitary Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D015175:Prolactinoma / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D051381:Rats; D013469:Sulpiride; D013752:Tetracycline / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism
chemical_list: D004967:Estrogens; D013469:Sulpiride; D014446:Tyrosine 3-Monooxygenase; D013937:Thymidine Kinase; D013752:Tetracycline; D004298:Dopamine