We have evaluated a number of compounds that influence the growth of lung cancer cells. We have reported previously on the autocrine role of gastrin releasing peptide, insulin-like growth factor, and transferrin. These factors stimulate growth for certain types of lung cancers. We have also shown that regulatory molecules such as glucagon and 13-cis- retinoic acid can inhibit the growth of a number of lung cancer cell lines. This experience has allowed us to focus on the signal transduction pathways most central to the process of cellular proliferation. In collaboration with Dr. M. Jett of the Walter Reed Army Research Institute, we have recently presented data suggesting that 5-HETE, a product of 5-lipoxygenase activation, may be a key intermediary in growth factor mediated growth stimulation of cancer cells. We have shown that lung cancer cells frequently express the message for 5- lipoxygenase. These cells also express an associated molecule critically required for lipoxygenase-mediated growth effects, five lipoxygenase activating protein (FLAP). We have shown that we can antagonize these pathways to reduce the growth of tumor cells using specific antagonists. We have demonstrated with an in vivo model that this anti-proliferative effect of blocking the lipoxygenase pathway permits re-expression of the growth inhibitory effect of apoptosis. This is important mechanistic information that will allow rapid translation into clinical prevention application. Several lipoxygenase inhibitors exist that could be available to evaluate in Phase I/II prevention trials, and we are comparing the in vitro and in vivo characteristics to decide the best candidate to take to clinical evaluation.
