Potential use of lipoxygenase inhibitors for cancer chemoprevention.
Increasing evidence suggests that lipoxygenase (LO)-catalysed metabolites have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO products have been found in breast tumours, colon cancers, lung, skin and prostate cancers, as well as in cells from patients with both acute and chronic leukaemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumour cell adhesion and regulation of apoptotic cell death. Agents that block LO catalytic activity may be effective in preventing cancer by interfering with signalling events 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 preventing the metabolic activation of carcinogens. Other compounds may work by negatively modulating DNA synthesis. Pharmacological profiles of potential chemopreventive agents are compiled from enzyme assays, in vitro testing (e.g., cell proliferation inhibition in human cancer cells) and in vivo animal 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 for chemoprevention trials in human subjects. Based on currently available data, it is expected that the prevention of lung and prostate cancer will be initially studied in human trials of LO inhibitors.
Steele
V E
VE
Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892, USA. vs1y@nih.gov
Holmes
C A
CA
Hawk
E T
ET
Kopelovich
L
L
Lubet
R A
RA
Crowell
J A
JA
Sigman
C C
CC
Kelloff
G J
GJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D018890:Chemoprevention / Q000379:methods; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D008084:Lipoxygenase / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D051381:Rats
D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D008084:Lipoxygenase