Replication-competent Adenovirus-mediated Suicide Gene Therapy with Radiation in a Preclinical Model of Pancreatic Cancer
Authors: Svend O Freytag, Kenneth N Barton, Stephen L Brown, Vinod Narra, Yingshu Zhang, Don Tyson, Colleen Nall, Mei Lu, Munther Ajlouni, Benjamin Movsas, Jae Ho Kim
Journal: Molecular Therapy (2007)

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/mutTKSR39rep-ADP adenovirus and also to the cytotoxic effects of the yeast cytosine deaminase (yCD) and herpes simplex virus thymidine kinase (HSV-1 TKSR39) genes in vitro. Combining Ad5-yCD/mutTKSR39rep-ADP-mediated suicide gene therapy with radiation significantly increased tumor control beyond that of either modality alone. Injection of Ad5-yCD/mutTKSR39rep-ADP in the dog pancreas at doses (1012 virus particle (vp)) to be used in humans resulted in mild pancreatitis but not peritonitis or hepatotoxicity. Following administration of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]-FHBG), a positron-emitting substrate of HSV-1 TK, Ad5-yCD/mutTKSR39rep-ADP activity could be monitored non-invasively by positron emission tomography (PET). [18F]-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/mutTKSR39rep-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. 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/mutTKSR39rep-ADP adenovirus and also to the cytotoxic effects of the yeast cytosine deaminase (yCD) and herpes simplex virus thymidine kinase (HSV-1 TKSR39) genes in vitro. Combining Ad5-yCD/mutTKSR39rep-ADP-mediated suicide gene therapy with radiation significantly increased tumor control beyond that of either modality alone. Injection of Ad5-yCD/mutTKSR39rep-ADP in the dog pancreas at doses (1012 virus particle (vp)) to be used in humans resulted in mild pancreatitis but not peritonitis or hepatotoxicity. Following administration of 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine ([18F]-FHBG), a positron-emitting substrate of HSV-1 TK, Ad5-yCD/mutTKSR39rep-ADP activity could be monitored non-invasively by positron emission tomography (PET). [18F]-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/mutTKSR39rep-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.