The objectives of this project are to develop new agents for the chemoprevention and treatment of lung cancer. Lung cancers, especially those with a neuroendocrine phenotype, have specific cell surface receptors for a variety of neuropeptides. Binding of the peptide to the receptor activates a specific signal transduction pathway characterized by activation of G-proteins, phospholipase C, diacylglycerol, protein kinase C (PKC) and liberation of intracellular calcium by inositol trisphosphate. Activation of PKC and other proteins by the increase in [Ca2+]i leads to transcription of specific genes (jun, fos, myc) and proliferation. the activating peptides may be produced by tumor cells themselves (autocrine) and by pulmonary epithelial cells (paracrine). Cigarette smoke increases the production of these peptides. In a Syrian hamster model of lung cancer, chemical carcinogens present in cigarette smoke produced neuroendocrine hyperplasia, elevated levels of bombesin, calcitonin and other peptides and neuroendocrine cancers. We and others showed that the signal transduction pathway induced by multiple peptides could be blocked by using substance P derivatives which appear to down regulate multiple peptide receptors and by using B8509-035 which is a calcium/calmodulin/PKC antagonist. These compounds inhibited the growth of lung cancer cell lines in vitro at concentrations considerably below those which inhibit breast cancer cell line growth. B8509-035 was shown to prevent the development of neuroendocrine hyperplasia and neuroendocrine tumors in the Syrian hamster model. It was also shown to be non-toxic in animals and humans. Non-toxic doses in animals gave concentrations which were well above those which inhibited lung cancer cell line growth in vitro. In this proposal, we will perform in vitro studies to further elucidate the mechanism of action of these compounds, perform in vivo animal studies to allow these compounds to enter human clinical trials alone and in combination and perform initial phase I and phase II studies in human patients with supportive laboratory evaluations.
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