Molecularly targeted approaches to the chemoprevention of lung cancer.

Large, randomized trials have been conducted in the primary prevention of lung cancer using micronutrients or derivative agents for which epidemiological data suggested a potential role in lung cancer prevention. The disappointing primary prevention trials of beta-carotene, alpha-tocopherol, and retinyl palmitate have led to the development of a more compact, biomarker-driven series of translational trials of lung cancer prevention that target reversal of premalignancy as the primary end point. Serial trials of 13-cis-retinoic acid (isotretinoin) and other retinoids have failed to show a difference in reversal of premalignancy in active smokers or in second primary tumor prevention. However, a trial of 9-cis-retinoic acid, a pan retinoid/rexinoid agonist, showed up-regulation of retinoic acid receptor beta (RAR-beta), a potentially important intermediate marker of response in lung cancer premalignancy. Other planned or ongoing trials currently target important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors, and the tyrosine kinase/epidermal growth factor receptor pathway (gefitinib, erlotinib). Early results of bioadjuvant trials in head and neck cancer suggest that combination chemoprevention will ultimately be an important option.