Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene

Background. Metastatic pancreatic cancer is uniformly fatal because no effective chemotherapy is available. Mutations in the p53 tumor suppressor gene are found in up to 70% of pancreatic adenocarcinomas. We examined the efficacy of a retroviral vector containing the wild-type p53 gene on metastatic pancreatic cancer in a nude mouse model. Methods. Bxpc3 human pancreatic cancer cells were transduced with either a retroviral p53 vector or an LXSN emtpy vector. Cells were examined for incorporation of triatiated thymidine to determine the effect of p53 retroviral transduction on DNA synthesis, and a TACS2 assay for apoptosis was performed. The functional activity of p53 in transduced cells was assayed by Western blot analysis with an antibody to WAF1/p21. In vivo effects of intraperitoneal injections of the p53 vector was examined in a nude mouse model of peritoneal carcinomatosis. Results. Cells treated with the p53 vector exhibited a 59% to 85.5% reduction in cell number comapred with the control cells (P < .05). p53-treated cells demonstrated decreased incorporation of tritiated thymidine (12.7% ± 0.7% vs 17.5% ± 1.4%; P = .002), increased staining for apoptosis, and increased expression of the WAF1/p21 protein. Treatment of nude mice with the retroviral p53 vector resulted in a significant inhibition of growth of the primary pancreatic tumor, as well as the peritoneal tumor deposits, compared with the LXSN control vector. Conclusions. Intraperitoneal delivery of a retroviral p53 vector may provide a nude treatment approach for peritoneal carcinomatosis from pancreatic cancer.