tetracycline and Pituitary-Neoplasms

After some initial disappointments, the field of gene therapy is now gaining confidence and momentum. Recent improvements in gene transfer techniques promise targeted and supra-threshold levels of transgene expression leading to the desired therapeutic effects. This increase in optimism has spread to thefield of diabetes research. Firstly, the recent developments in gene transfer techniques are now being tested on the pancreatic insulin producing beta-cell. For many gene therapy strategies in the treatment of diabetes, transfection of insulin producing cells is a prerequisite. Secondly, if efficient and safe vectors that transduce beta-cells in vivo or ex vivo are made available, autoimmune beta-cell destruction in type 1 diabetes could be prevented. In this strategy, it is envisaged that gene therapy will protect the remaining beta-cell mass in newly diagnosed diabetics or pre-diabetic individuals at a high risk of becoming diabetic from autoimmune destruction. Thirdly, attempts are being made to genetically engineer cells to become artificial beta-cells. Such cells could conceivably compensate for the lost endogeneous alpha-cell mass and restore a regulated insulin secretion. This review will attempt to predict the future of gene therapy in the treatment of diabetes.

Topics: Adjuvants, Immunologic; Animals; Apoptosis; Autoantigens; Autoimmune Diseases; Cell Division; Cell Line, Transformed; Cell Survival; Cytokines; Diabetes Mellitus, Type 1; DNA, Recombinant; Fas Ligand Protein; Fibroblasts; Genetic Therapy; Genetic Vectors; Graft Rejection; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Membrane Glycoproteins; Mice; Mice, Transgenic; Pancreatic Ducts; Perforin; Pituitary Neoplasms; Pore Forming Cytotoxic Proteins; Proinsulin; Protein Processing, Post-Translational; Tetracycline; Transfection; Transplantation, Heterologous; Transplantation, Homologous; Tumor Cells, Cultured

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.

Topics: Adenoviridae; Animals; Dopamine; Estrogens; Flow Cytometry; Gene Transfer Techniques; Genetic Therapy; Humans; Mice; Pituitary Neoplasms; Prolactinoma; Rats; Sulpiride; Tetracycline; Thymidine Kinase; Tumor Cells, Cultured; Tyrosine 3-Monooxygenase