A-79175

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.

SB 210661, (S)-N-hydroxy-N-[2,3-dihydro-6-(2,6-difluorophenylmethoxy)-3-benzofuranyl]urea, is a potent and selective inhibitor of 5-lipoxygenase. Its aqueous stability was primarily evaluated to support development of analytical methods and formulations. The results also add to the growing database on the stability of N-hydroxyurea compounds.Comparison of the stability of SB 210661 with that of two other N-hydroxyurea-containing compounds, zileuton and Abbott-79175, supported a common primary degradative pathway at pH > 5 and different degradative pathways at pH < 5. The pathway at pH > 5 is consistent with the hydrolysis of the N-hydroxyurea group, whereas for SB 210661, the pathway at pH < 5 is consistent with specific acid-catalysed nucleophilic displacement of the N-hydroxyurea group by water.