Potential use of lipoxygenase inhibitors for cancer chemoprevention

Increasing evidence suggests that lipoxygenase (LO)-catalysed metabolites h ave a profound influence on the development and progression of human cancer s. Compared with normal tissues, significantly elevated levels of LO produc ts have been found in breast rumours, colon cancers, lung, skin and prostat e cancers, as well as in cells from patients with both acute and chronic le ukaemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription fac tor activation, oncogene induction, stimulation of tumour cell adhesion and regulation of apoptotic cell death. Agents that block LO catalytic activit y may be effective in preventing cancer by interfering with signalling even ts needed for tumour growth. In the past ten years, pharmaceuticals agents that specifically inhibit the 5-LO metabolic pathway have been developed to treat inflammatory diseases such as asthma, arthritis and psoriasis. Some of these compounds possess anti-oxidant properties and may be effective in preventing cancer by blocking free radical-induced genetic damage or by pre venting the metabolic activation of carcinogens. Other compounds may work b y negatively modulating DNA synthesis. Pharmacological profiles of potentia l chemopreventive agents are compiled from enzyme assays, in vitro testing (e.g., cell proliferation inhibition in human cancer cells) and in vivo ani mal carcinogenesis models (e.g., N-methyl-N-nitrosourea-induced rat mammary cancer, benzo(a)pyrene induced lung tumours in strain A/J mice and hormone -induced prostate tumours in rats). In this way, compounds are identified f or chemoprevention trials in human subjects. Based on currently available d ata, it is expected that the prevention of lung and prostate cancer will be initially studied in human trials of LO inhibitors.