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 oral 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 would be limited by its spread and neurotoxicity, but it might be possible to develop mutants whose range could be restricted to oral cancers. Thus we have investigated the effects of HSV-1 on human oral cancer cells and have used both wild-type virus and a mutant that lacks UL42--an essential gene of the virus. Growth of the oral cancer cell line 686LN was readily inhibited by wild-type HSV-1, with only 10(2) plaque forming units (pfu) per milliliter required for 50% inhibition. In contrast, the mutant HSV-1 required a titer of 10(6) pfu/ml for 50% inhibition of growth. The mutant virus did, however, inhibit cell growth through the activation of ganciclovir and thus might be able to amplify its cytotoxicity through a bystander effect. When wild-type HSV-1 was injected into 686LN cells which were growing as tumors in nude mice, the virus spread through the tumor. Treated tumors were smaller, of lower weight, and significantly more necrotic than either untreated tumors or tumors which had been treated with the mutant virus. The wild-type virus spread to the skin and nervous system of most animals causing zosteriform skin rash, neurological symptoms and death, while the mutant virus produced 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 cells, and that controlled expression of the UL42 gene would be one way to obtain that limitation.
Shillitoe
E J
EJ
Department of Microbiology and Immunology, SUNY College of Medicine, Syracuse 13210, USA. shillitoe@hscsyr.edu
Gilchrist
E
E
Pellenz
C
C
Murrah
V
V
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy / Q000821:virology*; D002455:Cell Division; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D009154:Mutation / Q000235:genetics; D014407:Tumor Cells, Cultured; D014779:Virus Replication