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Factors That Limit the Effectiveness of Herpes Simplex Virus Type 1 for Treatment of Oral Cancer in Mice

Authors' Affiliation: Department of Microbiology and Immunology, SUNY College of Medicine, Syracuse, New York

Requests for reprints: Edward J. Shillitoe, Department of Microbiology and Immunology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210. Phone: 315-464-5453; Fax: 315-464-4417; E-mail: shillite{at}upstate.edu.

Although the growth of experimental oral cancers can be inhibited by infection with the herpes simplex virus type 1 (HSV-1), the effect is incomplete. To define factors that might limit the effectiveness of the virus, we examined the roles of the innate immune system and the replication status of the tumor cells. AT-84 tumors were induced in strains of mice that had specific immune defects and were treated with the virus. Explanted tumors and tumor cells in culture were also infected. No differences in viral replication or in the effect of virus on the tumor were seen between mice with a lack of T or B lymphocytes, natural killer cells, phagocytic spleen cells, or complement. The virus did not replicate significantly more in tumors that were maintained as explants. Immediately after recovery of cells from a tumor the proportion of cells in the S phase was around 18%, and replication of virus in those cells was very limited. After 3 weeks in culture, the proportion in S had increased to 50% and both the recovery of virus from the cells and the toxic effect of the virus on the cells had increased significantly.

The innate immune system thus seemed to have a minimal effect on replication of HSV-1 when used as an oncolytic virus for oral cancers in mice. Instead, the fraction of cells in the S phase was important. Because human oral cancers, like mouse tumors, have a low fraction of cells in the S phase, it is likely that the in vivo use of HSV-1 as cancer therapy will be limited by the replication of the virus.

Key Words: Oncolytic • DNA virus • virus vector