Effect of herpes simplex virus type-1 on growth of oral cancer in an immunocompetent, orthotopic mouse model.

Herpes simplex virus type-1 has been proposed as an agent for the treatment of oral cancer. Experiments were designed to test its effectiveness in an animal model that had a high level of similarity to the human disease. The mouse oral cancer cell line, AT-84, was implanted at an orthotopic site--the base of the tongue--into syngeneic, immunocompetent C3H mice. As expected, tumors invaded the musculature of the tongue, eroded the mandible, and metastasized to the lungs. To obtain a suitable strain of HSV-1 for therapy we screened 17 fresh clinical isolates and selected one that grew to a high titer in vitro. The mouse tumors were then treated by injection of HSV-1 at a titer of 10(9) plaque-forming units/milliliter. To prolong the anti-tumor effect some mice were also given cyclophosphamide, hydrocortisone, or a second injection of virus. To find the importance of bystander killing of tumor cells, some mice were given virus with ganciclovir. A reduction in tumor volume for a limited period was seen after treatment by HSV-1, and was increased by a second injection of virus or by the administration of cyclophosphamide. Ganciclovir negated the anti-tumor effect. Virus was detectable in the tumors for up to 7 days, and loss of virus coincided with the time at which growth of tumors resumed. The mortality of the mice varied up to around 50%. It appears that (1) a non-attenuated strain of HSV-1 can inhibit the growth of an aggressive malignant oral tumor, but only to a limited extent and (2) inhibition depends on the ability of the virus to replicate in the tumor. It is suggested that mutations in the virus will be necessary to prevent mortality, but must be designed carefully so as not to reduce the virulence of the virus.