General Principles And Safety Issues

The principle of suicide gene therapy stems from the long history of drug discovery and development focusing on the treatment of microbial infections. The enyzmes encoded by suicide genes are important components in metabolic conversion pathways within bacteria, viruses, or fungi (5). The effect of a prodrug on human cells that have been transduced with a suicide gene therefore parallels the effect of an antibiotic on a human bacterial infection. The microbial origin of these enzymes provide 2 important safety and specificity features of suicide gene-prodrug therapy that are similar or identical to the features of antibiotic or antiviral therapy. First, the en-yzmes and the associated metabolic pathway may be completely specific to microbial cells and not found in mammalian cells. Because mammalian cells lack the enzyme encoded by the suicide gene, systemic administration of the prodrug has no toxic effect on any human tissue or cell that has not been engineered to express the selected suicide gene (6). Second, certain mammalian cells may actually express the enyzme, but the specific prodrug chose may be a poor substrate for the mammalian form of the enzyme and an excellent substrate for the bacterial or viral form. Again in this scenario, administration of the prodrug would be harmless to the mammalian cell that has not been engineered to overexpress the nonmam-malian enzyme. The prodrug is therefore similar to or may actually be a form of antibiotic or antiviral medicine. Systemic administrations of the prodrug will produce effects limited to cells expressing the suicide gene and the microenvironment surrounding these cells and would not cause significant systemic toxicity.

Another general safety feature for suicide gene therapy lies within the actual mechanism of cytotoxicity that results from the conversion of the prodrug to a toxic metabolite. Because the majority of these metabolites inhibit cellular nucleic acid synthesis pathways, the delivery of the suicide gene and administration of the prodrug would have a preferential cyto-toxic affect on actively dividing cells. With respect to tumor cell populations vs. normal mammalian cells, the tumor would be more susceptible to the effects of suicide gene therapy. Some suicide gene therapy systems do not show preference for dividing cells, which raises a safety issue. Surrounding normal tissue may be inadvertently injured after exposure and subsequent transduction by the suicide gene. Selection and application of gene delivery techniques are therefore important in targeting the tumor while minimizing exposure to normal or systemic tissues to the suicide gene.

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