Even after smoking cessation, genetic damage in the airways epithelium may lead to focal progression of lung
carcinogenesis. Some centres now report as many new
lung cancer cases among former smokers as among current smokers.
Chemoprevention is a potential approach to diminish the progression of pre-clinical genetic damage. The most intensively studied
lung cancer chemoprevention agents are the
retinoids, including
vitamin A and its synthetic analogues and precursors. While effective in suppressing lung
carcinogenesis in animal models,
retinoids have failed to inhibit
carcinogenesis in human
chemoprevention trials with premalignant end-points (sputum atypia, bronchial
metaplasia). In trials with
lung cancer end-points, administration of
retinoids either was ineffective or, in the case of
beta-carotene, led to greater
lung cancer incidence and mortality. In view of these findings, markers of specific
retinoid effect (i.e., levels of
RAR-beta) become less relevant. Other markers of genetic instability and proliferation may be useful for both early detection and potentially as intermediate-effect markers for new
chemoprevention trials. Cytological atypia, bronchial
metaplasia,
protein (
hnRNP A2/B1) overexpression, ras oncogene activation and tumour-suppressor gene deletion,
genomic instability (loss of heterozygosity, microsatellite alterations), abnormal methylation, helical CT detection of atypical adenomatous
hyperplasia and fluorescent bronchoscopic detection of angiogenic squamous dysplasia offer great promise for molecular diagnosis of
lung cancer far in advance of clinical presentation. These end-points can now be evaluated as monitors of response to
chemoprevention as potential intermediate-effect markers.