ADENOVIRUS-MEDIATED GENE-THERAPY IN AN EXPERIMENTAL-MODEL OF BREAST-CANCER METASTATIC TO THE BRAIN

We investigated the therapeutic efficacy of adenovirus-mediated gene t herapy to treat malignant mammary tumors in vitro and in vivo in the b rain, A mammary adenocarcinoma cell line derived from Fischer rats (13 762 MAT B III; MAT-B) was used, In vitro studies demonstrated that the MAT-B cells could be efficiently transduced with a replication-defect ive adenovirus (ADV) vector that carried the herpes simplex virus gene for thymidine kinase (ADV-tk), and that ADV-tk transduction rendered the MAT-B cells sensitive to killing, in a dose-dependent manner, with ganciclovir (GCV), An animal model of a mammary tumor metastatic to t he brain was produced by injecting MAT-B cells into the caudate nucleu s of Fischer rats, Seven days after MAT-B cell injection, when the tum ors were approximately 5 mm(2) in cross-sectional size, the tumors wer e injected with ADV-tk or a control adenovirus vector containing the b eta-galactosidase (beta-Gal) gene (ADV-beta gal). After vector injecti on the animals were treated with GCV or with saline for 6 days, Sixtee n days after tumor cell injection, the brains were examined histologic ally, The rats that were injected with ADV-beta gal and treated with G CV or saline, and those that were injected with ADV-tk and treated wit h saline had large tumors, whereas the rats that were injected with AD V-tk and treated with GCV had no visible tumor tissue at the site of t umor cell injection, In survival studies animals treated with ADV-tk GCV survived a significantly longer time than animals treated with AD V-beta gal + GCV, Our results demonstrate that the recombinant adenovi ral vector containing the tk gene confers GCV cytotoxic sensitivity to mammary tumor cells in vitro and in the brain, and suggest that this treatment strategy may be useful in treating somatic tumors that metas tasize to the brain.