title: Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes.
abstract: Mutations in the p53 tumor suppressor gene and the pathways mediated by the p53 protein are common in many human cancers. Replacement of functional p53 by gene therapy is a potential way of combating these cancers and the associated drug resistance and tumor growth. Aerosol delivery of genes is a noninvasive way of targeting genes to the lung for gene therapy. Here we demonstrate, using a murine melanoma lung metastasis model, that aerosol delivery of polyethyleneimine-p53 (PEI-p53) complexes inhibits the growth of lung metastasis. A significantly reduced number of visible foci were observed in C57BL/6 mice injected with B16-F10 melanoma and treated with PEI-p53 complexes by aerosol for 3 weeks at twice a week. Fifty percent of the mice in the PEI-p53-treated group exhibited no visible tumor foci. There was a significant reduction in the lung weights of p53-treated mice (P < 0.01) compared to control groups. The tumor burden was also significantly lower (P < 0.001) in mice treated with PEI-p53 complexes. No extrapulmonary metastasis was observed in the groups treated with PEI-p53 complexes compared to 50% of the mice in control groups, which showed metastasis to lymph nodes in the neck or abdomen. Treatment with PEI-p53 aerosol also led to about a 50% increase in the mean length of survival of the mice injected with B16-F10 cells. These data suggest that delivery of the p53 gene by aerosol using PEI as the gene delivery vector can inhibit the growth of lung metastasis.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gautam
authors.forename: C L
authors.initials: CL
authors.lastname: Densmore
authors.forename: J C
authors.initials: JC
authors.lastname: Waldrep
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007275:Injections, Intravenous; D008156:Luciferases / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008546:Melanoma, Experimental / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D011094:Polyethyleneimine; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D016159:Tumor Suppressor Protein p53; D011094:Polyethyleneimine; D008156:Luciferases