title: Replication-competent adenovirus-mediated suicide gene therapy with radiation in a preclinical model of pancreatic cancer.
abstract: In preparation for a Phase I trial, we evaluated the efficacy and toxicity of replication-competent adenovirus-mediated suicide gene therapy in combination with radiation in a preclinical model of pancreatic cancer. Human MiaPaCa-2 and PANC-1 pancreatic adenocarcinoma cells were found to be sensitive to the oncolytic effects of the Ad5-yCD/mutTK(SR39)rep-ADP adenovirus and also to the cytotoxic effects of the yeast cytosine deaminase (yCD) and herpes simplex virus thymidine kinase (HSV-1 TK(SR39)) genes in vitro. Combining Ad5-yCD/mutTK(SR39)rep-ADP-mediated suicide gene therapy with radiation significantly increased tumor control beyond that of either modality alone. Injection of Ad5-yCD/mutTK(SR39)rep-ADP in the dog pancreas at doses (10(12) virus particle (vp)) to be used in humans resulted in mild pancreatitis but not peritonitis or hepatotoxicity. Following administration of 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]-FHBG), a positron-emitting substrate of HSV-1 TK, Ad5-yCD/mutTK(SR39)rep-ADP activity could be monitored non-invasively by positron emission tomography (PET). [(18)F]-FHBG uptake was readily detected in the pancreas but not in other major abdominal organs, indicating that little of the injected adenovirus disseminates to collateral tissues. These results demonstrate that Ad5-yCD/mutTK(SR39)rep-ADP-mediated suicide gene therapy has the potential to augment the effectiveness of pancreatic radiotherapy without resulting in excessive toxicity. Hence they provide the scientific basis for an ongoing Phase I trial in pancreatic cancer.
authors.affiliation: Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan 48202, USA. sfreyta1@hfhs.org
authors.forename: Svend O
authors.initials: SO
authors.lastname: Freytag
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Barton
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Brown
authors.forename: Vinod
authors.initials: V
authors.lastname: Narra
authors.forename: Yingshu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Don
authors.initials: D
authors.lastname: Tyson
authors.forename: Colleen
authors.initials: C
authors.lastname: Nall
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Munther
authors.initials: M
authors.lastname: Ajlouni
authors.forename: Benjamin
authors.initials: B
authors.lastname: Movsas
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D015774:Ganciclovir / Q000008:administration & dosage / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D049268:Positron-Emission Tomography; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects
chemical_list: D013937:Thymidine Kinase; D043525:Cytosine Deaminase; D015774:Ganciclovir