This laboratory is investigating regional approaches to in vivo gene delivery for the purpose of gene therapy. The principle obstacles to effective in vivo gene therapy for cancer are efficient gene delivery into the tumor, high levels of gene expression within cells, and selective expression within tumor cells compared to normal cells. In an attempt to address these essential factors we have designed a unique gene expression system and gene delivery system which is currently under investigation. In order to upregulate gene expression we have designed a gene construct that utilizes the prokaryotic T7 RNA polymerase which is expressed using a tissue specific promoter. The marker gene or suicide gene is expressed on a T7 promoter specific for the T7 RNA polymerase. This should allow an exponential upregulation of expression in a tissue selective fashion. This construct is currently under investigation in vitro using the adenovirus and liposome vectors. The ultimate plan is to deliver these vectors via regional perfusion techniques. Simultaneous with the development of these gene constructs we have developed animal models of regional perfusion. This includes the isolated limb perfusion in the nude rat which will allow tumor response data against human cell lines. We have also established a peritoneal carcinomatosis model in the nude mouse. For toxicity data we have established an isolated perfusion system in the pig. We utilize a cell- free electrolyte solution containing the vector of interest which is circulated through the isolated limb for 60 minutes with no evidence of leak. In addition to these studies we are interested in the treatment of human peritoneal carcinomatosis. We have established the technique of continuous hyperthermic peritoneal perfusion (CHPP) which is a procedure for treating peritoneal tumor at the time of surgical debulking and lysis of adhesions. A heated chemotherapy solution is circulated via a closed recirculation system through the peritoneal cavity. We have recently completed a phase I study of CHPP with cisplatin, establishing the maximum tolerated dose of cisplatin at 300 mg/M2. We have continuedthis technique in a Phase II trial as a neoadjuvant and intraoperative adjuvant for resectable gastric and pancreatic cancer. In addition, a new Phase I/II trial for gross peritoneal carcinomatosis examining CHPP with cisplatin followed by intraperitoneal Taxol and 5-FU was recently reviewed by the IRB.
