Nitrosamine-induced lung carcinogenesis and Ca2+/calmodulin antagonists.

This review summarizes recent data which implicate cell membrane receptors and their associated signal transduction pathways as molecular targets of tobacco-related lung carcinogenesis as well as therapy of such cancers. It is shown that the two nitrosamines N-nitrosodiethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone bind to nicotinic cholinergic receptors in hamster lung. Binding of the nitrosamines as well as nicotine to this receptor stimulates proliferation of human lung carcinoid cells in vitro. These data suggest chronic stimulation of nicotinic receptors by nicotine and nitrosamines in smokers as one of the molecular events responsible for stimulation of neuroendocrine cell proliferation and ultimately the development of lung tumors with neuroendocrine differentiation. On the other hand, a selective antiproliferative effect of the dihydropyridine derivative B859-35 on neuroendocrine lung tumor cells in vivo and in vitro suggests the potential use of such agents as cancer therapeutics. The demonstrated inhibition of Ca2+/calmodulin and protein kinase C by B859-35 as reported in other in vitro systems suggests interference with such elements of signal transduction pathways as the molecular mechanism of the observed antiproliferative effects.