Effects of novel 5-lipoxygenase inhibitors on the incidence of pulmonary adenomas in the A/J murine model when administered via nose-only inhalation.
The objective of this study was to determine the effects of 5-lipoxygenase (5-LO) inhibitors on the incidence of benzo(a)pyrene-induced pulmonary adenomas in female A/J mice. Two novel compounds, S-29606 and S-30621, and the Food and Drug Administration-approved Zileuton were investigated. S-29606 and S-30621 were selected from a group of similar active structures on the basis of local versus systemic 5-LO inhibitory activity. Preliminary studies found them to lack oral bioavailability, in direct contrast to Zileuton. Treatment was initiated 1 week following exposure to the carcinogen benzo(a)pyrene. Both S-29606 and S-30621 were dosed via nose-only inhalation 5 days a week, for 16 weeks, whereas Zileuton was administered orally. Dose levels for S-29606 and S-30621 were determined to be 220 and 430 microg/kg for the low- and high-dose groups, respectively, whereas the dose of Zileuton was 245 mg/kg. Both test compounds exhibited a significant reduction of pulmonary adenomas, compared with a positive control for high and low doses, P < 0.05. Additionally, a dose response for both S-29606 and S-30621 was observed when compared with placebo. Despite a dose 575 times greater than that of the novel test compounds, orally administered Zileuton did not produce a reduction in adenoma occurrence. The findings of this study offer compelling preliminary data for the use of S-29606 and S-30621 in further investigations of the treatment of pulmonary adenomas and support the use of inhalation drug delivery as an alternate to oral delivery for these compounds.
Myrdal
P B
PB
College of Pharmacy, University of Arizona, Tucson, AZ, USA.
Karlage
K
K
Kuehl
P J
PJ
Angersbach
B S
BS
Merrill
B A
BA
Wightman
P D
PD
D000236:Adenoma / Q000139:chemically induced / Q000517:prevention & control*; D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001564:Benzo(a)pyrene; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006877:Hydroxamic Acids / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015994:Incidence; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D010671:Phenylurea Compounds / Q000494:pharmacology
D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D010671:Phenylurea Compounds; C520943:S 29606; C520944:S 30621; D001564:Benzo(a)pyrene; C063449:zileuton; D006918:Hydroxyurea