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Titolo:
Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppressesgrowth of estrogen-induced pituitary prolactinomas
Autore:
Williams, JC; Stone, D; Smith-Arica, JR; Morris, ID; Lowenstein, PR; Castro, MG;
Indirizzi:
Univ Manchester, Sch Med, Mol Med & Gene Therapy Unit, Manchester M13 9PT,Lancs, England Univ Manchester Manchester Lancs England M13 9PT r M13 9PT,Lancs, England Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England Univ Manchester Manchester Lancs England M13 9PT M13 9PT, Lancs, England
Titolo Testata:
MOLECULAR THERAPY
fascicolo: 6, volume: 4, anno: 2001,
pagine: 593 - 602
SICI:
1525-0016(200112)4:6<593:RADOTH>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOPAMINE AGONISTS; GENE-THERAPY; BRAIN INFLAMMATION; FIRST-GENERATION; IN-VIVO; EXPRESSION; CELLS; ADENOMAS; RECEPTOR; CABERGOLINE;
Keywords:
tetracycline regulation; anterior pituitary; gene transfer/therapy; adenoviral vectors; lactotroph hyperplasia;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Castro, MG Cedars Sinai Med Ctr, Gene Therapeut Res Inst, 8700 Beverly Blvd, Los Angeles, CA 90048 USA Cedars Sinai Med Ctr 8700 Beverly Blvd Los Angeles CA USA 90048
Citazione:
J.C. Williams et al., "Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppressesgrowth of estrogen-induced pituitary prolactinomas", MOL THER, 4(6), 2001, pp. 593-602

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 controlthe 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 increaseof 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 31/03/20 alle ore 16:15:00