Enhancement of gene therapy specificity for diffuse colon carcinoma liver metastases with recombinant herpes simplex virus.

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OBJECTIVE: The authors determined whether a recombinant herpes simplex virus (HSV) vector could destroy human colon carcinoma cells in vitro and whether the vector would selectively replicate in colon carcinoma liver metastases but not surrounding hepatocytes in vivo. BACKGROUND: The HSV vector hrR3 is defective in the gene encoding ribonucleotide reductase and contains the lacZ reporter gene. Ribonucleotide reductase is expressed in actively dividing cells and generates deoxyribonucleotides for DNA synthesis. hrR3 replicates only in actively dividing cells that can provide ribonucleotide reductase in complementation, but not in quiescent cells such as normal hepatocytes. METHODS: hrR3-mediated lysis of HT29 human colon carcinoma cells was first determined in vitro. For in vivo studies, athymic BALB/c nude mice underwent intrasplenic injection of HT29 and intrasplenic injection of hrR3 7 days later, and were killed 7 days after viral injection. Their livers were examined histochemically for lacZ expression. RESULTS: All the HT29 cells were destroyed in vitro when hrR3 was added at a titer of 1 plaque-forming unit per 10 tumor cells. One hundred one of 105 tumor nodules examined in liver sections from mice treated by intrasplenic injection of hrR3 demonstrated lacZ expression. Minimal beta-galactosidase activity was present in normal liver. CONCLUSIONS: The hrR3 HSV vector effectively destroys HT29 human colon carcinoma cells at very low multiplicities of infection. Differential expression of ribonucleotide reductase between liver metastases and normal liver allows hrR3 to selectively replicate in tumor cells with minimal replication in surrounding normal liver. Further investigation of HSV-based vectors as oncolytic agents for liver metastases is warranted.

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