1. ¹Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan, USA
2. ²Department of Surgery, Ford Health System, Detroit, Michigan, USA
3. ³Alliance Health Imaging, Detroit, Michigan, USA
4. ⁴Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Michigan, USA

Correspondence: Svend O. Freytag, Department of Radiation Oncology, Henry Ford Health System, One Ford Place, 5D, Detroit, Michigan 48202, USA. E-mail: sfreyta1@hfhs.org

Received 13 December 2006; Accepted 17 April 2007; Published online 12 June 2007.

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_SR39rep-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_SR39rep-ADP-mediated suicide gene therapy with radiation significantly increased tumor control beyond that of either modality alone. Injection of Ad5-yCD/mutTK_SR39rep-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/mutTK_SR39rep-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/mutTK_SR39rep-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.