Increasing knowledge about molecular characteristics of malignant cells allows the development of gene therapeutic strategies against a variety of human tumors. Diverse approaches have been followed that can be classified into strategies directly aimed at the tumor or tumor cells, as well as strategies aimed toward the immune system of the host. Due to the successive accumulation of gene defects during tumor development, therapies based on direct gene transfer into tumor cells are mainly of destructive rather than of corrective nature. Suicide killing of tumor cells can be achieved by genetically modifying the malignant cells to express bacterial toxins, prodrug activating enzymes, or tumor suppressors (1,2). The expression of such therapeutics has to be highly restricted to the tumor cells to prevent damage of normal tissues. This selectivity can be achieved by the combination of tumor-targeted gene delivery with tumor-targeted gene transcription. Although transcriptional targeting systems for different tumors have been developed during recent years, tumor-restricted gene delivery is still an obstacle that has to be overcome (1,2).

However, tumor destruction via gene therapy is not exclusively dependent on direct gene transfer into the malignant cells, it can also be achieved by genetic strategies directed toward the immune system of the tumor-bearing host. The motivation of such immunotherapeutical approaches is based on findings, mainly obtained during treatment of melanoma patients, which clearly indicated that the immune system can specifically attack the tumor. Spontaneous regression of pri mary malignancies can be observed. In addition, tumor-infiltrating T lymphocytes that have the capability to specifically recognize and destroy autologous tumor cells can be isolated. A multitude of studies characterizing the immunogenic nature of tumors and immune responses of the host against it, led to the following concept of T cell-dependent antitumor immunity. Tumor cell destruction can be mediated by cytotoxic CD8+ T lymphocytes (CTLs), specifically recognizing epitopes derived from tumor antigens presented by MHC class I molecules on the surface of the malignant cell. CTL effector activity is dependent on helper functions of antigen-specific CD4+ T cells suggesting that an effective antitumor immune response essentially requires cell-mediated adaptive immunity of a Thl-like phenotype (3,4). Based on this model, immunization protocols are developed that trigger the immune system to overcome the hurdles of immunological tolerance against tumor antigens or escape mechanisms of the tumor. In this context, genetic vaccination might prove great potential. Here, vaccination is attained by administering eukaryotic expression plasmid encoding tumor antigens and/or immune stimulatory molecules in order to activate a cellular immune response directed against the malignant cells.

Irrespective of whether the genetic material is targeted to the immune system or to the tumor or tumor cells, efficient DNA delivery is an absolute requirement. Recently, bacteria have been discovered as an efficient tool for gene delivery to mammalian cells (5-7). This chapter focuses on 2 bacterial delivery systems, Listeria monocytogenes and Salmonella typhimurium, which had already proven their potential as carriers for heterologous antigens and are now employed in the delivery of expression plasmids to host cells in vitro and in vivo. In this chapter, the potential use of these bacteria as vector systems for tumor gene therapy is highlighted.

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