GENE-THERAPY FOR PERITONEAL DISSEMINATION OF PANCREATIC-CANCER BY LIPOSOME-MEDIATED TRANSFER OF HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE

Peritoneal dissemination is one of the most common complications of th e malignancies of the digestive system, such as gastric or pancreatic cancers. Yet, no effective therapy has been established so far to alle viate this devastating and often fatal end-stage condition, Here we de scribe a novel approach of intraperitoneal (i.p.) lipofection of a sui cidal gene to the pancreatic cancer cells in a mouse peritoneal dissem ination model. A human pancreatic cancer cell line, PSN-1, was inocula ted into the peritoneal cavity of nude mice, Eight days later, a herpe s simplex virus thymidine kinase (HSV-TK) gene expression plasmid unde r a potent hybrid promoter CAG was injected as a DNA-lipopolyamine com plex, Ganciclovir (GCV) was then administered for 8 days, and the mice were examined for tumor development at the 24th day after the tumor i noculation, Although all 24 control mice showed macroscopic peritoneal dissemination and solid tumors on the pancreas, 8 of the 14 mice trea ted with HSV-TK and GCV were free of tumors, and only a few small tumo rs were observed in the remaining 6 mice, Treatment-related toxicity w as not observed, The semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analysis suggested that the HSV-TK transgene was expressed in about 10% of tumor cells but not in the normal pancre as or in the small. intestine, When the lacZ gene was transduced in pl ace of the HSV-TK gene, the blue-stained cells were identified only in tumor nodules and not in normal organs, This preclinical study sugges ts the therapeutic feasibility of the i.p. lipofection-based suicidal gene/prodrug strategy for peritoneal dissemination of pancreatic cance r.