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Gene Therapy for Peritoneal Dissemination of Pancreatic Cancer by Liposome-Mediated Transfer of Herpes Simplex Virus Thymidine Kinase Gene

1997; Mary Ann Liebert, Inc.; Volume: 8; Issue: 9 Linguagem: Inglês

10.1089/hum.1997.8.9-1105

1557-7422

Kazunori Aoki, Teruhiko Yoshida, Nobuyuki Matsumoto, Hisamitsu Ide, Koichi Hosokawa, Takashi Sügimura, Masaaki Terada,

Renal and related cancers

Peritoneal dissemination is one of the most common complications of the malignancies of the digestive system, such as gastric or pancreatic cancers. Yet, no effective therapy has been established so far to alleviate this devastating and often fatal end-stage condition. Here we describe a novel approach of intraperitoneal (i.p.) lipofection of a suicidal gene to the pancreatic cancer cells in a mouse peritoneal dissemination model. A human pancreatic cancer cell line, PSN-1, was inoculated into the peritoneal cavity of nude mice. Eight days later, a herpes simplex virus thymidine kinase (HSV-TK) gene expression plasmid under a potent hybrid promoter CAG was injected as a DNA–lipopolyamine complex. Ganciclovir (GCV) was then administered for 8 days, and the mice were examined for tumor development at the 24th day after the tumor inoculation. Although all 24 control mice showed macroscopic peritoneal dissemination and solid tumors on the pancreas, 8 of the 14 mice treated with HSV-TK and GCV were free of tumors, and only a few small tumors were observed in the remaining 6 mice. Treatment-related toxicity was 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 pancreas or in the small intestine. When the lacZ gene was transduced in place of the HSV-TK gene, the blue-stained cells were identified only in tumor nodules and not in normal organs. This preclinical study suggests the therapeutic feasibility of the i.p. lipofection-based suicidal gene/prodrug strategy for peritoneal dissemination of pancreatic cancer. Peritoneal dissemination is an often fatal end-stage manifestation of pancreatic cancer, and patients with this condition are generally refractory to conventional therapeutic approaches. The present study showed the efficacy and safety of the lipofection-based herpes simplex virus thymidine kinase and ganciclovir (HSV-TK/GCV) approach to the pancreatic cancer cells disseminated in the peritoneal cavity. This suicidal gene therapy is expected to play a role in the future treatment of advanced pancreatic cancer.