Lung cancer continues to be the leading cause of cancer death in industrialized countries and there is an urgent need for the development of preventive treatments that inhibit the progression of initiated cells into overt lung cancer in smokers who quit. Murine pulmonary adenocarcinoma models are widely used to test prospective cancer preventive agents. These tumors are of alveolar type II cell lineage, express growth-regulating signal transduction pathways that are stimulated by epidermal growth factor and protein kinase C while being inhibited by agents that increase intracellular cyclic AMP (cAMP). By contrast, pulmonary adenocarcinomas induced in hamsters are derived from bronchial and bronchiolar Clara cells, are under beta-adrenergic receptor control and their development is promoted by agents that increase intracellular cAMP. Adenocarcinomas of either cell lineage develop in humans, raising the possibility that agents with strong chemopreventive activity in murine lung cancer models due to stimulation of cAMP may selectively promote human pulmonary adenocarcinomas derived from Clara cells. We therefore compared the effects of the beta-adrenergic agonist isoproterenol and the activator of cAMP forskolin under controlled in vitro conditions on the human pulmonary adenocarcinoma cell line NCI-H322 which expresses a Clara cell phenotype versus the human pulmonary adenocarcinoma cell line A549 which expresses features of alveolar type II cells. Our data show that isoproterenol significantly stimulated cAMP, ERK1/2 activity and DNA synthesis in NCI-H322 cells and that this response involved transactivation of the EGF receptor. By contrast, we found that isoproterenol had no effect on A549 cells whereas forskolin significantly inhibited DNA synthesis and ERK1/2 activity. Our findings are consistent with the interpretation that human pulmonary adenocarcinomas of Clara cell lineage are highly sensitive to the cancer promoting effects of beta-adrenergic agonists and other agents that stimulate cAMP whereas human cancers of the same histological family but derived from alveolar type II cells are resistant to beta-adrenergic agonists and respond with a reduction in cell growth to stimulation of cAMP. Our findings suggest that some widely advertised cancer preventive agents such as green tea, retinoids and beta-carotenes are unsafe to be used by smokers or by ex-smokers due to their tumor promoting effects via stimulation of cAMP on initiated cells of Clara cell lineage.