PubMed1995
To be effective, gene therapy requires three essential elements: a gene to transfer, a vector to carry the gene,and a target cell (here the cancer cell). One type of gene action of particular interest is the suicide gene. When introduced into the cell, the expression of this gene leads to cell death by production of pro-drugs. For example the gene for thymidine kinase from the type 1 herpes simplex virus (HSV1-TK) transforms nucleoside analogues such as ganciclovir into triphosphates which inhibit polymerases. When incorporated into deoxyribonucleic acid during cell division, DNA synthesis is arrested causing cell death. Thus only cells containing the HSV1-TK gene are sensitive to ganciclovir. The most widely used vectors are retroviruses. When these vectors infect a cell, the genes they carry are incorporated into the cell genome and, in the case of suicide genes, lead to cell death. These retrovirus vectors must however be transformed by genetic engineering to remove their capacity for replication so that no viral replication occurs, limiting the effect to the infected cell alone. In cancer therapy, retrovirus appears to be a choice vector since only cells undergoing active division, such as malignant tumour cells, are affected by the gene transfer. Primary or secondary liver tumours are a choice target for gene therapy for several reasons. First, cell division in these tumours is permanent and rapid while the surrounding healthy tissue is in a quiescent state. Secondly, gene therapy could be possible in man since extra-hepatic diffusion of the retrovirus could be avoided by temporary exclusion of the hepatic circulation during perfusion of the retrovirus. Although the long-term risks of using retrovirus vectors for gene therapy (effect on germ cells, oncogenesis), the effect on multiple or large tumours of the liver and the proliferative potential of residual tumour cells remain to be determined, gene therapy for liver cancer is now entering the stage where promising clinical applications may soon be proposed. We have applied gene therapy in in vivo experimental animal models with promising results suggesting that liver cancer may be one of the first applications of this new therapeutic tool in man.