GENE-THERAPY OF METASTATIC PANCREAS CANCER WITH INTRAPERITONEAL INJECTIONS OF CONCENTRATED RETROVIRAL HERPES-SIMPLEX THYMIDINE KINASE VECTOR SUPERNATANT AND GANCICLOVIR

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 p eritoneal metastases from pancreas cancer. Summary Background Data Met astatic pancreas cancer is fatal. Gene therapy may provide a novel app roach for this disease. Gene therapy with adeno- or retroviral-mediate d transfer of the HS-tk gene into tumor cells renders the cells suscep tible to GCV. Intratumoral or intracavity injections of retroviral vec tors have been ineffective in previous studies. Methods Pancreatic can cer BxPC3 cells (3 X 10(7)) were injected into the tail of pancreas in nude mice. Mice received IP injections of a concentrated HS-tk vector (5 X 10(7) 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 vec tor would survive in the milieu of the peritoneal cavity, the authors examined the effects of ascitic fluid on the vector. Pancreas cancer c ells were transduced in vitro with HS-tk vector in presence of media o r ascitic fluid and treated with GCV. Results Highly significant reduc tions in the mass of metastatic peritoneal tumor deposits were found i n HS-tk-treated group (124 +/- 27 mg; n = 11) compared with G1Na vecto r 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 me dia or ascitic fluid showed that the number of surviving colonies (rep resenting nontransduced cells) were similar in both groups, suggesting that the vector effectively transduced tumor cells bathed in the asci tic fluid. Conclusions Results demonstrate that IP administration of c oncentrated retroviral HS-tk vectors is effective treatment for pancre as cancer metastatic to the peritoneal cavity; furthermore, the vector is active in the presence of ascitic fluid, Intraperitoneal retrovira l HS-tk may provide a novel approach to treatment of metastatic pancre as cancer.