Neuroendocrine cancer and peripheral adenocarcinoma are the most common histological lung cancer types linked with smoking. The nicotine-derived nitrosamine, 4-(methylnitrosamino)-1-(2-pyridyl)-1- butanone (NNK) is among the most abundant and potent carcinogens contained in cigarette smoke. NNK induces a high incidence of peripheral adenocarcinomas in the lungs of laboratory rodents maintained under ambient air conditions while it causes lung cancers of neuroendocrine differentiation when administered to hyperoxic hamsters. Having shown that NNK binds to nicotinic cholinergic and beta-adrenergic receptors in hamster lung and lung cancer cell lines Dr. Schuller proposes to study the effects of NNK on mitogenic signal transduction pathways stimulated by these receptor types.
Specific Aim Having shown that NNK-induced mitogenesis of cell lines derived from peripheral pulmonary adenocarcinomas involves binding to beta adrenergic receptors (b-AR) and activation of cyclic AMP, Dr. Schuller will study the acute and chronic effects of NNK on this signal transduction pathway in vitro using normal and NNK transformed human bronchial cells and normal hamster Clara cells as well as cell lines derived from human and hamster lung adenocarcinomas as model systems.
