Targeted expression of toxic genes directed by pituitary hormone promoters: A potential strategy for adenovirus-mediated gene therapy of pituitary tumors

Pituitary adenomas cause clinical manifestations because of mass effects and excess hormone production. This group of tumors represents a tractable target for gene therapy because they are rarely metastatic and because reductions in tumor size and function, in addition to those achieved after surgery, may be of clinical benefit. In this report we describe a strategy for targeting the expression of toxic genes to pituitary cells using adenoviral vectors. Pituitary hormone promoters (human GH or glycoprotein hormone α-subunit) were used to express either a marker gene [β- galactosidase (β-gal)] or a toxic gene [herpes simplex virus thymidine kinase (TK)]. In GH-producing GH₃ cells and in α-subunit-producing pituitary tumor cell lines, recombinant adenoviruses containing either the α-subunit promoter (AdαGal; AdαTK) or the GH promoter (AdGHGal; AdGHTK) were expressed at high levels. Using histological studies and assays for β- gal activity, expression was shown to persist for at least 21 days, and it was relatively selective for pituitary cell lines. Cytotoxicity studies were performed using the TK-containing vectors and treatment with ganciclovir. Both AdGHTK and AdαTK caused greater than 95% cytotoxicity of GH₃ and αT3 cells, respectively, at a viral dose (multiplicity of infection, 5 plaque- forming units/cell) that induced minimal toxicity using control viruses. Little cellular toxicity was seen using a nonpituitary cell line (T47D breast tumor cells). The AdGHTK virus also caused marked reduction in the size of GH₃ cell tumors that were propagated in nude mice. These studies suggest that adenoviral vectors carrying human pituitary gland specific promoters may be useful for developing gene therapy strategies for the treatment of pituitary adenomas.