Abstract
We devised an aerosol based demethylation therapy to achieve therapeutic efficacy in premalignant or in situ lesions of lung cancer, without systemic toxicity. Optimum regimens of aerosolized azacytidine (Aza) were designed and used in orthotopic human non-small cell lung cancer xenograft models. The therapeutic efficacy and toxicity of aerosol Aza were compared with intravenously administered Aza. We observed that 80% of the droplets of the aerosol Aza measured ∼0.1–5 microns, which resulted in deposition in the lower bronchial airways. An animal model that phenocopies field carcinogeneisis in humans was developed by intratracheal inoculation of the human lung cancer cells in mice, thus resulting in their distribution throughout the entire airway space. Aerosolized Aza significantly prolonged the survival of mice bearing endo-bronchial lung tumors. The aerosol treatment did not cause any detectable lung toxicity or systemic toxicity. A pre-pharmacokinetic study in mice demonstrated that lung deposition of aerosolized Aza was significantly higher than the intravenous route. Lung tumors were resected after aerosol treatment and the methylation levels of 24 promoters of tumor-suppresser genes related to lung cancer were analyzed. Aerosol Aza significantly reduced the methylation level in 9 of these promoters and reexpressed several genes tested. In conclusion, aerosol Aza at non-cytotoxic doses appears to be effective and results in DNA demethylation and tumor suppressor gene re-expression. The therapeutic index of aerosol Aza is >100-fold higher than that of intravenous Aza. These results provide a preclinical rationale for a phase I clinical trial of aerosol Aza to be initiated at our Institution.
Highlights
Lung cancer claims 1.4 million lives every year [1,2]
Upon the demonstration that tumor suppressor genes (TSGs) deactivation and oncogene activation play a critical role in carcinogenesis, the therapeutic efforts have progressively shifted from optimizing the non-specific radiation and chemotherapy forms of therapy that mainly kill fast-dividing cells to develop agents that target the specific genetic changes
Recent evidence suggests a direct relationship between aberrant epigenetic changes and cancer development; it indicates that cancer is in part an epigenetic disease
Summary
Lung cancer claims 1.4 million lives every year (http://www. who.int/mediacentre/factsheets/fs297/en/index.html) [1,2]. Lung cancer claims 1.4 million lives every year Lung cancer occurs as a result of cumulative damage in the bronchial epithelium caused by inhaled carcinogens. Because the cumulative damage affects the entire airway, damaged airway epithelium is prone to develop additional primary tumors during an individual’s lifespan [3]. All non-small cell lung cancers (NSCLC) originate from the bronchial epithelium covering large or small airways, giving rise to central or peripheral tumors. Squamous cell lung carcinomas most often arise centrally in large bronchi, lung adenocarcinomas typically develop peripherally in the smaller airways, and large cell lung carcinomas may arise in either location. All tumors originate from transformed airway epithelial cells. Selective therapeutic intervention for tumors confined to the airways should effectively inhibit or delay their formation without causing systemic toxicity [4,5,6,7]. No therapies targeting the bronchial epithelium are currently available
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