Insulin-like growth factor-I gene therapy reverses morphologic changes and reduces hyperprolactinemia in experimental rat prolactinomas.

Gloria M Console,Rodolfo G Goya,Gisela A Camihort,Gustavo R Morel,Maria I Bracamonte,Claudia B Herenu,Georgina C Luna

doi:10.1186/1476-4598-7-13

Abstract

BackgroundThe implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors. Up to now, suicide gene therapy has been the main experimental approach explored to treat experimental pituitary tumors. In the present study we assessed the effectiveness of insulin-like growth factor I (IGF-I) gene therapy for the treatment of estrogen-induced prolactinomas in rats.ResultsFemale Sprague Dawley rats were subcutaneously implanted with silastic capsules filled with 17-β estradiol (E2) in order to induce pituitary prolactinomas. Blood samples were taken at regular intervals in order to measure serum prolactin (PRL). As expected, serum PRL increased progressively and 23 days after implanting the E2 capsules (Experimental day 0), circulating PRL had undergone a 3–4 fold increase. On Experimental day 0 part of the E2-implanted animals received a bilateral intrapituitary injection of either an adenoviral vector expressing the gene for rat IGF-I (RAd-IGFI), or a vector (RAd-GFP) expressing the gene for green fluorescent protein (GFP). Seven days post vector injection all animals were sacrificed and their pituitaries morphometrically analyzed to evaluate changes in the lactotroph population. RAd-IGFI but not RAd-GFP, induced a significant fall in serum PRL. Furthermore, RAd-IGFI but not RAd-GFP significantly reversed the increase in lactotroph size (CS) and volume density (VD) induced by E2 treatment.ConclusionWe conclude that IGF-I gene therapy constitutes a potentially useful intervention for the treatment of prolactinomas and that bioactive peptide gene delivery may open novel therapeutic avenues for the treatment of pituitary tumors.

Highlights

The implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors
Effect of insulin-like growth factor I (IGF-I) gene therapy on pituitary lactotroph morphology Stereotaxic injection of RAd-green fluorescent protein (GFP) into pituitary adenomas induced a significant expression of GFP around the track of the needle (Fig. 1) without significantly damaging the gland (Fig. 1, inset)
Lactotroph volume density (VD) was higher in estrogen-induced pituitary adenomas when compared with the pituitaries of intact animals (Fig. 4)

Summary

Introduction

The implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors. In the present study we assessed the effectiveness of insulin-like growth factor I (IGF-I) gene therapy for the treatment of estrogen-induced prolactinomas in rats. Pituitary adenomas constitute the most frequent neuroendocrine pathology in humans, comprising up to 15% of primary intracranial tumors [1] and are the most prevalent pathology in old female rats [2]. It has been shown that in primary cultures of rat lactotrophs, estrogen has an antiproliferative action in the presence of insulin or IGF-I [12,13] In view of this evidence, it was of interest to determine whether in vivo overexpression of the gene for rat IGF-I in estrogen-induced rat prolactinomas could be able to restore lacotropic cell morphology and reverse hyperprolactinemia.

Methods

Results

Conclusion