Cancer gene therapy: principles, problems, and perspectives

Despite enormous efforts focused on the development of new drugs and the use of novel drug combinations, including high-dose regimens supported by bone marrow and blood stem cell transplantation procedures, progress in the treatment of disseminated human cancer has been marginal. Remarkable advances in our understanding of the molecular biology of cancer has provided the possibility to employ new, selective tools of genetic intervention for more successful tumor treatment. We are now witnessing the inception of gene therapy. However, gene therapists face many drawbacks, including selectivity, specificity, sensitivity, and safety of gene transfer. Despite this there are already over 70 clinical protocols accepted for genetic approaches to cancer worldwide. Strategies currently under clinical investigation and discussed here include: (a) the enhancement of tumor immunogenicity by insertion of cytokine genes, genes coding for products of the major histocompatibility complex, and those for lymphocyte costimulatory ligands, (b) the vectoring of tumoricidal cytokines into cells that can potentially home on tumors to release their toxic products locally, (c) the use of tumor-specific pro-drug activators, i.e., the insertion of enzymatically pro-drug-activating genes fused to promoter systems which rely on differential (ideally tumorspecific) transcription control, (d) gene-marking strategies which may provide new indicators for minimal, residual, and relapsed tumor disease, (e) artificial repression of gene functions by insertion of genes encoding for complementary (antisense) mRNA to the gene of interest (e.g., oncogenes, drug resistance genes).