The clinical utility of any cancer treatment is defined by both its antitumoral potency and its therapeutic index between cancerous and normal cells. Chemotherapy for metastatic solid tumors generally fails due to an insufficient therapeutic index and/or insufficient antitumoral potency. Although standard agents target a variety of different structures within cancer cells, almost all of them are thought to kill cancer cells through the induction of apoptosis. As a result, apoptosis-resistant clones develop following standard therapies, even if numerous high-dose chemotherapeutic agents are used in combination. Novel therapeutic approaches must therefore have not only greater potency and greater selectivity than currently available treatments, they should also have novel mechanisms of action that will not be subject to cross-resistance with existing approaches (ie efficacy should not be exclusively dependent on apoptosis induction in cancer cells).

Replication-selective oncolytic viruses (virotherapy) appear to have these characteristics. Viruses have evolved to infect cells, replicate, induce cell death, release of viral particles, and finally to spread in human tissues. Replication in tumor tissue leads to amplification of the input dose at the tumor site, while a lack of replication in normal tissues can result in efficient clearance and reduced toxicity (Figure 1). Selective replication within tumor tissue can theoretically increase the therapeutic index of these agents dramatically. In addition, viruses kill cells by a number of unique mechanisms. In addition to direct lysis at the conclusion of the replicative cycle, viruses can kill cells through expression of toxic proteins, induction of both inflammatory cytokines and T-cell-mediated immunity, and enhancement of cellular-sensitivity to their effects. Therefore, since activation of classical apoptosis pathways in the cancer cell is not the exclusive mode of killing, cross-resistance with standard chemotherapeutics or radiotherapy is much less likely to occur. Revolutionary advances in molecular biology and genetics have led to a fundamental understanding of both (1) the replication and pathogenicity of viruses and (2) carcinogenesis. These advances have allowed novel agents to be engineered to enhance their safety and/or their antitumoral potency. Over the past decade, genetically-engineered viruses in development have included adenoviruses, herpesviruses and vaccinia. Viruses with inherent tumor-selectivity have been characterized and include reovirus, autonomous parvoviruses, Newcastle disease virus, measles virus strains and vesicular stomatitis virus (Kirn, 2000a). Each of these agents has shown tumor selectivity in vitro and/or in vivo, with many of these agents following intratumoral, intraperitoneal and/or intravenous routes of administration.