Chemopreventive therapeutics. Inhalation therapies for lung cancer and bronchial premalignancy

The lung cancer epidemic is not expected to abate in the next two decades. Smoking cessation campaigns have not been successful in reducing the prevalence of smoking to < 25% of the adult population in the US. Among high school students, the prevalence of smoking is increasing (27.5% in 1991; 36.4% in 1997) (43). In addition, only 1 in 8 heavy smokers develop lung cancer and about 20% of patients with lung cancer have no history of active or passive smoking, thus indicating that genetic predisposing factors and other unidentified carcinogens play a crucial role in the etiology of this disease. The bronchial epithelium is like an internal skin where lung cancer originates after chronic exposure to airborne carcinogens in a predisposed host. Although the bronchial epithelium is not readily examinable, it is easily accessible to therapeutic intervention by using inhaled therapeutics. We hope to extend our findings using direct wild-type p53 gene replacement via intratracheal and aerosolized administrations in mice to NSCLC patients with p53 mutations. We also plan on utilizing aerosolized chemical agents to activate endogenous mechanisms of cytoprotection. If, in clinical trials, evidence of effective cytoprotection is observed in the absence of intolerable side effects, further exploration of this new strategy for the control and prevention of a neoplastic disease that accounts for a third of all cancer-related deaths will be fully justified.