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

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Abstract
We investigated the therapeutic efficacy of adenovirus-mediated gene therapy to treat malignant mammary tumors in vitro and in vivo in the brain. A mammary adenocarcinoma cell line derived from Fischer rats (13762 MAT B III; MAT-B) was used. In vitro studies 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 mm2 in cross-sectional size, the tumors were injected with ADV-tk or a control adenovirus vector containing the β-galactosidase (β-Gal) gene (ADV-βgal). 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-βgal 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-βgal + GCV. Our results demonstrate that the recombinant adenoviral 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 metastasize to the brain. Transduction with a recombinant adenovirus carrying the gene for herpes simplex virus thymidine kinase (ADV-tk) followed by systemic administration with ganciclovir (GCV) had a robust tumoricidal effect on experimental mammary tumors in the brain. The mammary adenocarcinoma cell line, MAT-B, derived from a Fischer rat was used to generate model metastatic mammary tumors that were lethal to the hosts. When treated with ADV-tk and GCV these tumors regressed and the hosts lived significantly longer than controls. Secondary tumors distal to the injection site were not affected and eventually killed the hosts. These data suggest that this treatment strategy may be useful in treating tumors that metastasize to the brain.