title: Recombinant interferon alpha2a synergistically enhances ganciclovir-mediated tumor cell killing in the herpes simplex virus thymidine kinase system.
abstract: The herpes simplex virus thymidine kinase (HSV-TK) gene is being developed in the treatment of many different types of tumors. The HSV-TK gene sensitizes tumor cells to the antiviral drug ganciclovir (GCV) and mediates the bystander effect in which unmodified tumor cells are killed as well. Although this approach has shown a significant antitumor effect, the need to potentiate this therapy exists. The results of this study indicate that recombinant interferon alpha2a (1FNalpha2a) acts synergistically with GCV to kill HSV-TK-expressing PA1 human ovarian tumor cells. Furthermore, it enhances the bystander killing of nearby unmodified tumor cells that do not express the HSV-TK gene. Previous studies have suggested that in vitro and in vivo bystander effects may be mediated by different mechanisms. However, IFNalpha2a enhanced bystander killing in both systems, with the survival of mice bearing preexisting tumors being significantly prolonged when they were treated with IFNalpha2a and HSV-TK/GCV compared with either treatment alone. Mechanism studies have shown that treatment with IFNalpha2a and GCV caused an increase in cells in S phase 24 hours after therapy in the HSV-TK-expressing cells, but the mechanism of action of IFNalpha2a does not seem to be related to an increase in DNA damage, because GCV incorporation was not increased after treatment with IFNalpha2a. These findings suggest that IFNalpha2a may be a useful adjunctive therapy for the HSV-TK/GCV system.
authors.affiliation: Department of Medicine, Rhode Island Hospital and Brown University, Providence 02903, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Whartenby
authors.forename: J W
authors.initials: JW
authors.lastname: Darnowski
authors.forename: S M
authors.initials: SM
authors.lastname: Freeman
authors.forename: K
authors.initials: K
authors.lastname: Yurasha
authors.forename: P
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology / Q000628:therapy*; D015774:Ganciclovir / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D011994:Recombinant Proteins; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir