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 empty vector. Cells were examined for incorporation of tritiated 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 assessed by Western blot analysis with an antibody to WAF1/p21. In vivo effects of intraperitoneal injections of the p53 vector were 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 compared 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 novel treatment approach for peritoneal carcinomatosis from pancreatic cancer.
Department of Surgery, University of Southern California, Los Angeles 90033, USA.
R F
RF
Hwang
E M
EM
Gordon
W F
WF
Anderson
D
D
Parekh
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000556:secondary* / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000628:therapy; D012190:Retroviridae; D012867:Skin; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000166:cytology / Q000187:drug effects
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors