Regulated, adenovirus-mediated delivery of tyrosine hydroxylase suppressesgrowth of estrogen-induced pituitary prolactinomas

Prolactin-secreting adenomas are one of the most common types of intracrani al 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 prolactino mas that are difficult to treat. As an alternative, we have developed a gen e 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 lactotrop h growth and prolactin secretion, we developed a system that would enable i ts local synthesis from freely available precursor amino acids. A dual aden ovirus tetracycline-regulatable expression system was generated to control the production of TH. In the absence but not presence of the tetracycline a nalog 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 e xpression of TH was seen in lactotrophs, somatotrophs, corticotrophs, thyro trophs, and gonadotrophs in the absence but not presence of doxycycline. Th e ability of this system to inhibit hyperprolactinemia and pituitary lactot roph hyperplasia was then assessed in a model of estrogen- or estrogen/sulp iride-induced pituitary tumors. In the absence but not presence of doxycycl ine, 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 enha ncement gene therapy can be a useful tool for the treatment of prolactinoma . Dopamine synthesis can be tightly regulated and the therapeutic benefit o f the system is only inhibited when local dopamine signaling is impaired.