title: Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization.
abstract: Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic viral therapy to be combined with double suicide gene therapy. Both the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific cytopathic effects of the Ad5-CD/TKrep virus in vitro and sensitized cells to radiation. To extend these in vitro findings in vivo, we evaluated the antitumor activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant antitumor activity against C33A cervical carcinoma xenografts. Therapeutic outcome was dramatically improved with systemic administration of double, but not single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5-CD/TKrep-mediated double suicide gene therapy dramatically potentiated the effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral, double suicide gene, and radiotherapies produced significant tumor regression and ultimately 100% tumor cure. The results demonstrate the high therapeutic potential of the trimodal approach and provide a solid foundation for future clinical trials.
authors.affiliation: Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Rogulski
authors.forename: M S
authors.initials: MS
authors.lastname: Wing
authors.forename: D L
authors.initials: DL
authors.lastname: Paielli
authors.forename: J D
authors.initials: JD
authors.lastname: Gilbert
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: S O
authors.initials: SO
authors.lastname: Freytag
mesh_terms: D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics* / Q000502:physiology; D000818:Animals; D019677:Artificial Gene Fusion; D002470:Cell Survival; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D018259:Herpesvirus 1, Human / Q000201:enzymology; D015552:Injections, Intralesional; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000532:radiotherapy / Q000628:therapy*; D009700:Nucleoside Deaminases / Q000235:genetics; D011836:Radiation Tolerance; D013937:Thymidine Kinase / Q000235:genetics; D014779:Virus Replication
chemical_list: D013937:Thymidine Kinase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase