EFFECTIVE TREATMENT OF EARLY ENDOBRONCHIAL CANCER WITH REGIONAL ADMINISTRATION OF LIPOSOME-P53 COMPLEXES

Background: Lung cancer originates in a diffusely damaged bronchial ep ithelium as a result of sequential and cumulative genetic alterations. We investigated the feasibility of in vivo gene replacement in endobr onchial precancerous and cancerous cells by a regionally administered nonviral delivery system. Methods: After evaluating the in vitro trans fection efficiency and cytotoxicity of a variety of cationic liposome- p53 formulations, a specific formulation, DP3-p53, was selected for fu rther in vitro and in vivo evaluation. The ability of DP3-p53 to intro duce the p53 gene in the normal bronchial epithelium was studied in tr ansgenic mice that lack the p53 gene. The therapeutic effect of DP3-p5 3 administered intratracheally was studied in two nude mouse models of endobronchial human lung cancer by use of H358 (p53-null) and H322 (p 53-mutant) cells. Results: DP3-p53 was able to effectively introduce a nd express the p53 gene and induce G(1) arrest and apoptosis in H358 c ells ill vitro and to introduce and transcribe the p53 gene in the bro nchial epithelium of transgenic mice that lack the p53 gene in vivo. I n therapeutic experiments using groups of four or five mice each, admi nistration of five intratracheal doses of DP3-p53 (2 mu g or 8 mu g DN A per dose) on days 4, 8, 12, 16, and 20 after intratracheal tumor ino culation significantly inhibited lung tumor formation and prolonged by approximately twofold the survival of mice bearing H358 or H322 endob ronchial tumor cells in contrast to the survival among untreated mice and mice treated,vith the DP3-empty vector (P = .007 [two-sided log-ra nk test] for mice bearing H358 cells and P = .008 [two-sided log-rank test] for those bearing H322 cells). Conclusions/Implications: Liposom e-based p53 delivery through the airways is a potentially effective st rategy for the treatment of early endobronchial cancer. These results have important implications for the gene therapy and prevention of hum an lung cancer.