Carcinogenesis Advance Access originally published online on November 17, 2006
Carcinogenesis 2007 28(5):957-961; doi:10.1093/carcin/bgl216
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Effects of novel 5-lipoxygenase inhibitors on the incidence of pulmonary adenomas in the A/J murine model when administered via nose-only inhalation
College of Pharmacy, University of Arizona, Tucson, AZ, USA
1 3M Pharmaceuticals, 3M Center, St Paul, MN, USA
* To whom correspondence should be addressed. Tel: +1 520 626 3847; Fax: +1 520 626 4063; Email: kuehl{at}pharmacy.arizona.edu
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 µg/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.
Abbreviations: HPLC, high-performance liquid chromatography; 5-LO, 5-lipoxygenase; LT, leukotriene
Received July 11, 2006; revised October 4, 2006; accepted October 27, 2006.