Gene Therapy of Metastatic Pancreas Cancer with Intraperitoneal Injections of Concentrated Retroviral Herpes Simplex Thymidine Kinase Vector Supernatant and Ganciclovir

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Abstract
Objective The objective of this study was to determine the efficacy of intraperitoneal (IP) injections of a new concentrated herpes simplex thymidine kinase (HS-tk) retroviral vector and ganciclovir (GCV) for peritoneal metastases from pancreas cancer. Summary Background Data Metastatic pancreas cancer is fatal. Gene therapy may provide a novel approach for this disease. Gene therapy with adeno- or retroviral-mediated transfer of the HS-tk gene into tumor cells renders the cells susceptible to GCV. Intratumoral or intracavity injections of retroviral vectors have been ineffective in previous studies. Methods Pancreatic cancer BxPC3 cells (3 × 107) were injected into the tail of pancreas in nude mice. Mice received IP injections of a concentrated HS-tk vector (5 × 107 cfu/mL) or a control vector (G1Na) without the tk gene for 10 days and GCV (100 mg/kg) for 14 days. To determine whether the vector would survive in the milieu of the peritoneal cavity, the authors examined the effects of ascitic fluid on the vector. Pancreas cancer cells were transduced in vitro with HS-tk vector in presence of media or ascitic fluid and treated with GCV. Results Highly significant reductions in the mass of metastatic peritoneal tumor deposits were found in HS-tk-treated group (124 ± 27 mg; n = 11) compared with G1Na vector controls (910 ± 168 mg; n = 8; p < 0.0001). Results of polymerase chain reaction analysis demonstrated integration of the vector in the tumors, and on immunohistochemistry, expression of the TK protein was seen in the treated tumors. Exposure of the tumor cells in vitro to media or ascitic fluid showed that the number of surviving colonies (representing nontransduced cells) were similar in both groups, suggesting that the vector effectively transduced tumor cells bathed in the ascitic fluid. Conclusions Results demonstrate that IP administration of concentrated retroviral HS-tk vectors is effective treatment for pancreas cancer metastatic to the peritoneal cavity; furthermore, the vector is active in the presence of ascitic fluid. Intraperitoneal retroviral HS-tk may provide a novel approach to treatment of metastatic pancreas cancer.