Lipoxygenase inhibitors as potential cancer chemopreventives

Mounting evidence suggests that lipoxygenase (LO)-catalyzed products have a profound influence on the development and progression of human cancers. Co mpared with normal tissues, significantly elevated levels of LO metabolites have been found in lung, prostate, breast, colon, and skin cancer cells, a s well as in cells from patients with both acute and chronic leukemias. LO- mediated products elicit diverse biological activities needed for neoplasti c cell growth, influencing growth factor and transcription factor activatio n, oncogene induction, stimulation of tumor cell adhesion, and regulation o f apoptotic cell death. Agents that block LO-catalyzed activity mag be effe ctive in preventing cancer by interfering with signaling events needed for tumor growth. In fact, in a few studies, LO inhibitors have prevented carci nogen-induced lung adenomas and rat mammary gland cancers. During the past 10 years, pharmacological agents that specifically inhibit the LO-mediated signaling pathways are now commercially available to treat inflammatory diseases such as asthma, arthritis, and psoriasis, These well- characterized agents, representing two general drug effect mechanisms, are considered good candidates for clinical chemoprevention studies. One mechan ism is inhibition of LO activity (5-LO and associated enzymes, or 12-LO); t he second is leukotriene receptor antagonism. Although the receptor antagon ists have high potential in treating asthma and other diseases where drug e ffects are clearly mediated by the leukotriene receptors, enzyme activity i nhibitors may be better candidates for chemopreventive intervention, becaus e inhibition of these enzymes directly reduces fatty acid metabolite produc tion, with concomitant damping of the associated inflammatory, proliferativ e, and metastatic activities that contribute to carcinogenesis. However, be cause receptor antagonists have aerosol formulations and possible antiproli ferative activity, they may also have potential, particularly in the lung, where topical application of such formulations is feasible.