Cancer of the lung is the most prevalent cause of cancer related deaths in the United States. The products of the lipoxygenase (LOX) pathway of arachidonic acid (AA) metabolism have been linked with tumor growth and proliferation. It is unclear at the present time, however, if the state of the LOX products which result in tumor growth and proliferation is the result of absolute levels of specific LOX products or the result of an imbalance in one or more of the products in relation to each other. The overall objectives of the proposed research are to develop an analytical method capable of rapidly and accurately analyzing levels of LOX products and to elucidate the involvement of the LOX pathway in relation to the growth and development of lung cancer. This research is designed to examine the following hypotheses: first, samples of lung tissue, from in vivo experiments, can be analyzed for minute quantities of specified structurally similar products of the LOX pathway in a rapid manner; second, the LOX pathway is involved in the growth and proliferation of lung cancer and therefore, measurable changes in the products of the pathway will occur as tissue becomes cancerous. These hypotheses will be examined using the female A/J murine model in a triphasic approach. The first phase will be to develop and validate a high-throughput analytical method for the products of the LOX pathway in lung tissue from in vivo experiments and to establish base-line LOX product levels for the A/J mouse. The second phase will be to determine the differences in LOX product expression between pulmonary adenomas vs. histologically normal tissue in the lungs of a mouse that has received carcinogen vs. lung tissue from a mouse that has not been exposed to carcinogen. The third phase will examine the differences in LOX product expression between two different carcinogens, benzo(a)pyrene and vinyl carbamate. The long-term goals of this research are to fully elucidate the involvement and mechanisms of the LOX pathway in tumor progression and to utilize this knowledge to accomplish the following: determine the potentially beneficial targets in this pathway for drug development, expedite the development of compounds which show promise in affecting the levels and profile of the LOX products in a beneficial manner, and to examine the possibility of utilizing the measurement of LOX product profiles as a tool for early detection of cancer in patients.
