This application is based on the observation that a large proportion of lung cancer patients stop smoking prior to diagnosis, often prior to the onset of clinical symptoms, and characteristically without apparent difficulty. This has led to the hypothesis that some lung cancers produce a factor(s) which blocks addiction to nicotine. The goal of the proposed research is to determine whether human lung cancer cells produce a substance which interacts with the brain receptors which are involved in nicotine addiction. Preliminary studies utilizing a collection of human lung cancer cell lines, many of them established from patients who have stopped smoking prior to diagnosis, have identified several cell lines which produce a substance which binds to brain nicotinic receptors. This factor can be readily isolated using high performance liquid chromatography (HPLC). The current application is to purify sufficient quantities of the factor for structural analysis. Once the structure has been elucidated, the factor will be synthesized for detailed pharmacological and functional characterization. An assay for the factor will be developed which can be applied to human plasma and tumor samples. This assay will be used in clinical studies correlating the levels of this factor with smoking cessation history in lung cancer patients. The next step will be to determine whether this substance affects brain addiction pathways, or interferes with a rodent model of nicotine addiction. This research could lead to new strategies for smoking cessation. The discovery of a novel substance produced within the human body which interferes with nicotine addiction could have many basic, clinical, as well as commercial applications.
