Experimental adenoviral “suicide” gene therapy for CNS malignancies

Introduction: A promising approach for the treatment of CNS tumors is the transfer of the “suicide” herpes simplex virus-thymidine kinase (TK) gene into tumor cells followed by Ganciclovir (GCV) treatment. Adenoviral vectors have a few advantages over the commonly used retroviral vectors for this approach. Recombinant adenoviruses were constructed and tested in vitro in human cancer cells occurring as CNS tumors and in vivo using experimental brain tumor and leptomeningeal rat models. Methods: Adenoviral vectors with either the human cytomegalovirus (CMV) immediate early promoter or Adenovirus type 2 major late promoter (MLP), harbouring a marker gene (LacZ, luciferase) or a “suicide” TK gene were constructed. Differences in promoters, marker gene expression and GCV killing efficiency after TK gene transfer was evaluated in several human tumor cells in vitro and experimental rat brain tumor and leptomeningeal metastases in vivo. Results: Gene expression and tumor cell kill was very efficient in vitro and in vivo. Rats treated with recombinant adenoviruses containing the TK gene followed by GCV treatment showed significantly longer survival time (brain tumors) or symptom free period (leptomeningeal metastases). Recombinant adenoviruses containing the CMV promoter showed a significant more potent effect as compared to the MLP promoter in vitro and in vivo. Conclusions: This study demonstrates the therapeutic efficiency and feasibility of the suicide gene therapy approach in experimental brain tumors and leptomeningeal metastases. It also demonstrates that the promoter driving the transgene in an adenoviral vector influences expression and efficiency of treatment.