1. ¹Regional Cancer Program, Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada
2. ²Departments of Biology and Chemistry, Lakehead University, Thunder Bay, Ontario, Canada
3. ³Groupe de Vecteurs de G|[eacute]|nomique et Th|[eacute]|rapie G|[eacute]|nique, Biotechnology Research Institute, National Research Council, Montr|[eacute]|al, Quebec, Canada
4. ⁴INRS-IAF, Universit|[eacute]| du Qu|[eacute]|bec, Laval, Quebec, Canada
5. ⁵D|[eacute]|partement de Microbiologie et Immunologie, Facult|[eacute]| de M|[eacute]|decine, Universit|[eacute]| de Montr|[eacute]|al, Quebec, Canada
6. ⁶Department of Radiation Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada
7. ⁷Division of General Internal Medicine, University of Calgary, Alberta, Canada
8. ⁸Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada

Correspondence: Dr J Th'ng, Regional Cancer Program, Thunder Bay Regional Health Sciences Centre, 980 Oliver Road, Thunder Bay, P7B 6V4, Ontario, Canada. E-mails: thngj@tbh.net or jpht2001@yahoo.ca

Received 7 December 2005; Revised 10 March 2006; Accepted 22 April 2006; Published online 28 July 2006.

Abstract

A promising approach for cancer gene therapy is the combination of adenovirus vectors (AdV) with the suicide gene cytosine deaminase and uracil phosphoribosyl transferase (CD|[Colon]|UPRT). While such vectors have been tested in tumor cell lines and xenograft models, it is not clear how these therapeutic vectors would perform in primary human tumors. We, thus, examined the effect of the combination of a recombinant adenovirus expressing the CD|[Colon]|UPRT (AdCU) with 5-fluorocytosine (5-FC) on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers. In such models, we have found a direct correlation between the patients' response to 5-FU and the response shown by the cancer cells in vitro, confirming the clinical relevance of this methodology. Our findings demonstrated that this combination was able to kill primary tumor cells, including those that had developed resistance to 5-FU. Furthermore, while proliferating cells were more susceptible to 5-FU, the combination was effective in both rapid and slow proliferating samples. Our study demonstrated that this gene therapy approach could provide an effective therapeutic option for cancers and is not affected by acquired 5-FU resistance. Also of importance is the effectiveness of this gene therapy approach on slower proliferating cells that is typical of the majority of cancers in vivo. This suggests a greater likelihood that it will be effective in a clinical setting.