Carcinogenesis, Vol 19, 1393-1400, Copyright © 1998 by Oxford University Press
N Rioux and A Castonguay
5-Lipoxygenase is a key enzyme in the metabolism of arachidonic acid to
leukotrienes. The preventive efficacy of 5-lipoxygenase inhibitors against
lung tumorigenesis was determined in A/J mice given the tobacco- specific
carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in drinking
water from week 0 to week +7. Groups of 25 mice were fed either:
acetylsalicylic acid (ASA), a cyclooxygenase inhibitor; A- 79175, a
5-lipoxygenase inhibitor; MK-886, an inhibitor of the 5- lipoxygenase
activating-protein; a combination of ASA and A-79175 from weeks -2 to +23.
ASA, A-79175 and MK-886 reduced lung tumor multiplicity by 44, 75 and 52%
respectively. Furthermore, A-79175 reduced tumor incidence by 20%.
Administration of A-79175 and MK-886 decreased the mean tumor volume by 64
and 44% respectively. Lung tumor multiplicity was directly proportional to
tumor volume. The combination of ASA and A-79715 was the most effective
preventive intervention and reduced lung tumor multiplicity by 87% and lung
tumor incidence by 24%, demonstrating that inhibition of both
5-lipoxygenase and cyclooxygenase is more effective than inhibition of
either pathway alone. NNK treatment increased plasma prostaglandin E2
levels from 49 to 260 pg/ml and plasma LTB4 levels from 29 to 71 pg/ml.
Incubation of 82-132 and LM2 murine lung tumor cells with MK-886 and
A-79715 decreased cell proliferation in a concentration-dependent manner.
Soybean lipoxygenases with or without murine lung microsomal proteins
metabolized NNK by alpha-carbon hydroxylation (9.5% of the metabolites) and
N-oxidation (3.9%). Activation of NNK by alpha-carbon hydroxylation was
inhibited by addition of arachidonic acid and A-79715. Possible mechanisms
of action of 5-lipoxygenase inhibitors include inhibition of tumor growth
and lipoxygenase-mediated activation of NNK. These studies suggest that
inhibitors of 5-lipoxygenase may have benefits as preventive agents of lung
tumorigenesis.
ARTICLES
Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents
Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada.
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|
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|
|
|
|
|
|
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|
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|
|
|
|
 |
|
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|
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|
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|
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|
|
|
|
|
|
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|
|
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|
|
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|
|
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|
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