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*Genes and Gene Therapy
The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1296-1305
Copyright © 2000 by The Endocrine Society

Original Studies

Adenovirus-Mediated Herpes Simplex Virus Type-1 Thymidine Kinase Gene Therapy Suppresses Oestrogen-Induced Pituitary Prolactinomas1

S. Windeatt2, T. D. Southgate2, R. A. Dewey, F. Bolognani3, M. J. Perone, A. T. Larregina4, T. C. Maleniak, I. D. Morris, R. G. Goya, D. Klatzmann, P. R. Löwenstein and M. G. Castro

Molecular Medicine and Gene Therapy Unit, School of Medicine (S.W., T.D.S., R.A.D., F.B., M.J.P., A.T.L., T.C.M., P.R.L., M.G.C.), and School of Biological Sciences (I.D.M.), University of Manchester, Manchester M13 9PT, United Kingdom; and INIBIOLP-Histology "B", Faculty of Medicine (R.G.G.), National University of La Plata, La Plata, Argentina; and Department of Immunology, Hopital Pitie-Salpetriere (D.K.), Paris, France

Address correspondence and requests for reprints to: M. G. Castro, Molecular Medicine and Gene Therapy Unit, School of Medicine, University of Manchester, Room 1.302, Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom. E-mail: mcastro{at}fs1.scg.man.ac.uk

We tested the hypothesis that gene transfer using recombinant adenovirus vectors (RAds) expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) might offer an alternative therapeutic approach for the treatment of pituitary prolactinomas that do not respond to classical treatment strategies. HSV1-TK converts the prodrug ganciclovir (GCV) to GCV monophosphate, which is in turn further phosphorylated by cellular kinases to GCV triphosphate, which is toxic to proliferating cells. One attractive feature of this system is the bystander effect, whereby untransduced cells are also killed. Our results show that RAd/HSV1-TK in the presence of GCV is nontoxic for the normal anterior pituitary (AP) gland in vitro, but causes cell death in the pituitary tumor cell lines GH3, a PRL/GH-secreting cell line, and AtT20, a corticotrophic cell line. We have used sulpiride- and oestrogen-induced lactotroph hyperplasia within the rat AP gland as an in vivo animal model. Intrapituitary infection of rats bearing oestrogen-induced lactotroph hyperplasia, with RAd/HSV1-TK and subsequent treatment with GCV, decreases plasma PRL levels and reduces the mass of the pituitary gland. More so, there were 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 the HSV1-TK transgene could be further developed as a useful treatment to complement current therapies for prolactinomas.




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