Gene therapy of salivary gland carcinoma with virus vector

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Recurrence and regional and systemic metastases of salivary gland carcinoma occur frequently, and this condition is generally refractory to chemotherapy and radiotherapy. In order to treat these advanced cases, novel therapy is required. Gene therapy is one of the approaches for the treatment of these cases. Although viruses used for gene therapy are usually genetically modified to deliver therapeutic transgenes and prevent viral infection, replication-competent herpes simplex virus type 1 (HSV-1) may be also used for cancer therapy because replication of HSV-1 within cancer cells can result in their destruction.hrR3 virus has a lacZ insertion into the HSV-1 ICP6 gene. The ICP6 gene encodes the large subunit of HSV ribonucleotide reductase, and loss of its expression decreases the ability of the hrR3 to replicate in nondividing cells and increases specificity for tumor cell lysis. To obtain more effective HSV-1 mutant for the treatment of salivary gland carcinoma, we selected a fusion-inducing mutant hrR3f after repeated passages of hrR3 in Vero cells and human salivary gland adenocarcinoma HSY cells. When HSY cells were infected with hrR3 or hrR3f at a low input MOI, hrR3f could degenerate tumor cells more efficiently as compare with hrR3, because cells adjacent to hrR3f-infected cells were readily involved in polykaryocyte formation. Xenograft tumors were established in the subcutaneous tissue of the franks of nude mice, using HSY cells. A schedule consisting of multiple repeated percutaneous injection of hrR3f virus, to a total of three doses, was well tolerated and found inhibit tumor growth completely in the nude mouse model.These studies have demonstrated the ability of theHSV-1 mutants to inhibit salivary gland carcinomas.