PERONE Marcelo Javier
Adenovirus-mediated herpes simplex virus type-1 thymidine kinase gene therapy suppresses oestrogen-induced pituitary prolactinomas
WINDEATT, S; SOUTHGATE, TD; DEWEY, RA; BOLOGNANI, F; PERONE, MJ; LARREGINA, A. T.; MALENIAK, TC; MORRIS, ID; GOYA, RG; KLATZMANN, D; LOWENSTEIN, PR; CASTRO, MG
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
We tested the hypothesis that gene transfer using recombinantadenovirus vectors (RAds) expressing herpes simplex virus type 1thymidine kinase (HSV1-TK) might offer an alternative therapeuticapproach for the treatment of pituitary prolactinomas that do notrespond to classical treatment strategies. HSV1-TK converts the prodrugganciclovir (GCV) to GCV monophosphate, which is in turnfurther phosphorylated by cellular kinases to GCV triphosphate,which is toxic to proliferating cells. One attractive feature of thissystem is the bystander effect, whereby untransduced cells are alsokilled. Our results show that RAd/HSV1-TK in the presence of GCVis nontoxic for the normal anterior pituitary (AP) gland in vitro, butcauses cell death in the pituitary tumor cell lines GH3, a PRL/GHsecretingcell line, and AtT20, a corticotrophic cell line. We have usedsulpiride- and oestrogen-induced lactotroph hyperplasia within therat AP gland as an in vivo animal model. Intrapituitary infection ofrats bearing oestrogen-induced lactotroph hyperplasia, with RAd/HSV1-TK and subsequent treatment with GCV, decreases plasmaPRL levels and reduces the mass of the pituitary gland. More so, therewere no deleterious effects on circulating levels of other AP hormones,suggesting that the treatment was nontoxic to the AP gland in situ.In summary, our results show that suicide gene therapy using theHSV1-TK transgene could be further developed as a useful treatmentto complement current therapies for prolactinomas.