Effects of herpes simplex virus on human oral cancer cells, and potential use of mutant viruses in therapy of oral cancer

The herpes simplex virus type-1 (HSV-1) might be useful in treatment of ora l cancer because it is strongly cytolytic, and its natural target tissue is the source of oral squamous cell carcinomas. Use of a wild-type virus woul d be limited by its spread and neurotoxicity, but it might be possible to d evelop mutants whose range could be restricted to oral cancers. Thus we hav e investigated the effects of HSV-1 on human oral cancer cells and have use d both wild-type virus and a mutant that lacks UL42-an essential gene of th e virus. Growth of the oral cancer cell line 686LN was readily inhibited by wild-type HSV-I, with only 10(2) plaque forming units (pfu) per milliliter required for 50% inhibition. In contrast, the mutant HSV-I required a tite r of 10(6) pfu/ml for 50% inhibition of growth. The mutant virus did, howev er, inhibit cell growth through the activation of ganciclovir and thus migh t be able to amplify its cytotoxicity through a bystander effect. When wild -type HSV-I was injected into 686LN cells which were growing as tumors in n ude mice, the virus spread through the tumor. Treated tumors were smaller, of lower weight, and significantly more necrotic than either untreated tumo rs or tumors which had been treated with the mutant virus. The wild-type vi rus spread to the skin and nervous system of most animals causing zosterifo rm skin rash, neurological symptoms and death, while the mutant virus produ ced none of these side-effects. These results show that HSV-1 might be used to treat oral cancer if its replication could be limited to the tumor cell s, and that controlled expression of the UL42 gene would be one way to obta in that limitation. (C) 1999 Elsevier Science Ltd. All rights reserved.