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MO04 - Lung Cancer Biology I (ID 86)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
MO04.04 - Aerosol Azacitidine Reduces Methylation Levels of Tumor Suppressor Genes and Prolongs Survival in the Orthotopic Lung Cancer Models in Mice. (ID 1621)
16:15 - 17:45 | Author(s): Y. Liang
Promoter hypermethylation plays an important role in lung cancer carcinogenesis by silencing key tumor suppressor genes (TSG). Reversing the hypermethylation of TSG by direct aerosolized administration of a demethylating agent may have a potential to inhibit lung cancer growth and development. This study examines the therapeutic potential of aerosolized azacytidine (Aza) in the orthotopic mice model of human NSCLC.
Vidaza® (the clinical grade Aza formulation for IV administration) was dissolved into sterile water for injection and aerosolized in a clinical standard aerosol system. The aerodynamic size, the lung deposition, and the Aza level in the lung and circulation of mice were measured by previously described methods. The demethylation and gene reactivation functions of aerosolized Aza were detected by qPCR methylation array and western blotting assay in the human non-small cell lung cancer (NSCLC) tumor tissues from the orthotopic intratracheally inoculated xenograft models in nude mice. The therapeutic efficacy and toxicity of the aerosolized Aza were also evaluated in mice. Mice treated with an intravenously administered Aza with clinically equivalent dose and schedules were used as a comparison.
The aerosolized Aza is an appropriate pharmaceutical inhalation formulation with size distribution of about 80% of droplets from 0.1 to 5 micron. This dynamic size range ensures the aerosol droplets depositing in the lower airway as indicated by the recovery of approximately 80% Aza from the lung tissue 20 min after the aerosol administration. In efficacy and toxicity studies, aerosol administration of Aza significantly prolonged the survival of nude mice with intratracheally inoculated human NSCLC tumors. The %-increased in life span was 5- to 10-fold higher than that of a systemic treatment of Aza at a clinically equivalent dose. The aerosolized Aza, at a potentially therapeutic dose, did not cause any detectable lung toxicity or systemic toxicity (myelosuppression). After the aerosolized Aza treatment, the lung tumors were resected and the methylation levels of the 24 promoters driving the lung cancer related tumor suppressor genes (TSGs) in the lung tumors were examined by qPCR methylation array. The aerosolized Aza significantly reduced the methylation level in 9 of the 24 promoters examined. This demethylating effect also resulted in the gene reactivation at the protein level in several tested genes.
In our orthotopic NSCLC model, aerosolized Aza was well tolerated with good drug delivery to bronchial epithelium at non-cytotoxic doses. The pharmacodynamic effect of the TSG demethylation and reactivation was observed. Interesting therapeutic efficacy of prolonging survival was observed in our model from aerosolized 5-Aza over intravenous administration in mice. The phase I clinical trial of aerosolized Aza with pharmacodynamic endpoints will be conducted. Acknowledgement: Supported by a NIH (NCI) grant 5R01CA154755-02
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