Study of gene therapy for lymph node metastasis of oral squamous cell carcinoma

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Approximate 30 % of oral cancer patients have cervical lymph node metastasis. It is very hard to treat multiple metasatsis of superficial lymph nodes and regrowth of lymph node lesions. Oncolytic virotherapy with a replication-competent herpes simplex virus type 1 (HSV-1) is a promising approach for the treatment of such lymph node lesions, because HSV-1 strain HF10 was reported to be effective for lymph node metastasis of mammary cancer. We inoculated oral squamous cell carcinoma (SCC) cells derived from a metastatic lymph node subcutaneously into buccal area of nude mice and made a model system of cervical lymph node metastasis and lung metastasis. As agents for oncolytic virotherapy for oral SCC, γ_134.5-deficent mutant R849 and HF, the original strain of HF10, were tested for anti-tumor activity in oral SCC cells. Both R849 and HF could replicate and cell viability was decreased in a time-dependent manner. Cell rounding was observed in R849-infected cells, whereas HF induced multinuclear giant cells. However, the virus yield of R849 was higher than that of HF. When R849 was infected with R849 and cultured in the presence of hexamethylene bisacatamide (HMBA), a differentiating agent of leukemia, the virus production was increased markedly. The anti-tumor effect of R849 was also examined with the use of nude mouse model of oral SCC by injecting R849 into the tumors alone or in combination with intraperitoneal injection of HMBA. The tumor growth was suppressed by R849 treatment and the effect was further enhanced with HMBA. Inflammation response to HSV-1 infection produces oxygen radicals at the infection site. We demonstrated that hydrogen peroxide enhanced the release of HSV-1 from infected cells.