title: Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation.
abstract: Herpes simplex virus type 1 (HSV-1)-based oncolytic treatment is a promising therapeutic approach for malignancy. Recombinant strains of HSV-1 containing mutations in the ICP 34.5 protein have been shown to replicate preferentially in rapidly proliferating malignant cells, resulting in a direct cytolytic effect. We assessed the efficacy of multimutated HSV-1 strains on human cervical cancer, and then used these viruses in combination with radiation therapy, the standard treatment for cervical cancer. The HSV-1 mutants 4009, 7020, 3616, and G207 induced significant lysis of three established human cervical cancer cell lines in vitro in a dose-dependent manner. G207 intratumoral treatment of established subcutaneous C33a tumors in severe combined immunodeficient (SCID) mice significantly reduced tumor burden by 50%. Weekly and triweekly treatments improved efficacy and inhibited flank tumor growth in an administration frequency-dependent manner without toxicity. Combination therapy of a low dose of radiation (1.5 or 3 Gy) and replication-selective HSV mutants infection exhibited increased antitumor effects against cervical cancer cells in vitro. The in vivo effect of G207 combined with low-dose radiation was studied in Me180 xenografts in athymic mice. Treatment of established Me180 tumor nodules with 3 Gy followed by intratumoral G207 administration greatly improved efficacy, resulting in 42% complete eradication of tumor. In conclusion, single and multiple intratumoral injections of G207 significantly reduced tumor burden in xenogeneic models of cervical cancer, and the addition of low-dose radiation further potentiated the effect. These results suggest that replication-selective HSV-1 mutants may be potent oncolytic agents for the treatment of cervical cancer.
authors.affiliation: Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA. stephanie.blank@med.nyu.edu
authors.forename: Stephanie V
authors.initials: SV
authors.lastname: Blank
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Rubin
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.forename: Kunjlata M
authors.initials: KM
authors.lastname: Amin
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Molnar-Kimber
mesh_terms: D000818:Animals; D001691:Biological Therapy; D016923:Cell Death; D003131:Combined Modality Therapy; D005260:Female; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D011829:Radiation Dosage; D011878:Radiotherapy; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1