Adenovirus-Mediated Gene Therapy in an Experimental Model of Breast Cancer Metastatic to the Brain

ABSTRACTWe investigated the therapeutic efficacy of adenovirus-mediated gene therapy to treat malignant mammary tumors in vitroand in vivoin the brain. A mammary adenocarcinoma cell line derived from Fischer rats (13762 MAT B III; MAT-B) was used. In vitrostudies demonstrated that the MAT-B cells could be efficiently transduced with a replication-defective 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 the brain was produced by injecting MAT-B cells into the caudate nucleus of Fischer rats. Seven days after MAT-B cell injection, when the tumors were approximately 5 mm2in cross-sectional size, the tumors were injected with ADV-tk or a control adenovirus vector containing the -galactosidase (-Gal) gene (ADV-gal). After vector injection the animals were treated with GCV or with saline for 6 days. Sixteen days after tumor cell injection, the brains were examined histologically. The rats that were injected with ADV-gal and treated with GCV or saline, and those that were injected with ADV-tk and treated with saline had large tumors, whereas the rats that were injected with ADV-tk and treated with GCV had no visible tumor tissue at the site of tumor cell injection. In survival studies animals treated with ADV-tk GCV survived a significantly longer time than animals treated with ADV-gal GCV. Our results demonstrate that the recombinant adenoviral vector containing the tkgene confers GCV cytotoxic sensitivity to mammary tumor cells in vitroand in the brain, and suggest that this treatment strategy may be useful in treating somatic tumors that metastasize to the brain.