In small cell lung cancer, arachidonic acid is metabolized by lipoxygenase to 5-HETE and leukotriene A4. In contrast, arachidonic acid is metabolized by cyclooxygenase (COX) to prostaglandins (PGs) in non-small cell lung cancer (NSCLC). Here the effects of non-steroidal antiinflammatory drugs (NSAIDs) were investigated on lung cancer cells. Aspirin, ibuprofen and indomethacin inhibited NSCLC growth in vitro. Because indomethacin was the most potent inhibitor its effects on NSCLC growth was investigated in vivo. Indomethacin (5 ug/day, i.o.) slowed NSCLC xenograft growth in nude mice. Also, indomethacin prevented lung carcinogenesis in A/J mice induced by benzapyrene. These data suggest that NSAIDs may be chemopreventive agents for lung cancer. Two types of COX enzymes are present in lung cancer cells. COX-1 mRNA was detected in all NSCLC cell lines examined. COX-2 mRNA was present in NCI-H1264 as well as H157 cells and the levels were increased by epidermal growth factor (EGF). Indomethacin reduced PGE2 levels and EGF reversed the effects of NSAIDs. PGE2 stimulated the growth of NSCLC cells and the growth effects of PGE2 were reversed by NSAIDs. These data suggest that some of the growth promoting properties of EGF may be result from increased COX-2 expression. The biodistribution of COX enzymes was investigated in lung cancer biopsy specimens using immunocytochemical techniques. COX-1 was detected in the cytosol of both normal and malignant lung. COX-2 was detected in the cytosol and nucleus of malignant lung. The nuclear COX-2 may mediate the proliferation of NSCLC cells.
