Inhibition of experimental lung metastasis by aerosol delivery of PEI-p53 complexes.
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.
Gautam
A
A
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Densmore
C L
CL
Waldrep
J C
JC
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
D016159:Tumor Suppressor Protein p53; D011094:Polyethyleneimine; D008156:Luciferases