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Carcinogenesis Advance Access published online on November 17, 2006
Carcinogenesis, doi:10.1093/carcin/bgl216
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 11, 2006
Revised October 4, 2006
Accepted October 27, 2006

CANCER PREVENTION

Effects of Novel 5-Lipoxygenase Inhibitors on the Incidence of Pulmonary Adenomas in the A/J Murine Model when Administered via Nose-Only Inhalation

P.B. Myrdal 1, K. Karlage 1, P.J. Kuehl 1 *, B.S. Angersbach 1, B.A. Merrill 2, and P. D. Wightman 2

1 College of Pharmacy, University of Arizona, Tucson, AZ
2 3M Pharmaceuticals, 3M Center, St. Paul, MN

* To whom correspondence should be addressed.
P.J. Kuehl, E-mail: kuehl{at}pharmacy.arizona.edu


  Abstract

The objective of this study was to determine the effects of 5-lipoxygenase 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 FDA approved Zileuton, were investigated. S-29606 and S-30621 were selected from a group of similar active structures on the basis of local vs. systemic 5-lipoxygenase inhibitory activity. Preliminary studies found them to lack oral bioavailability, in direct contrast to Zileuton. Treatment was initiated one week following exposure to the carcinogen, benzo(a)pyrene. Both S-29606 and S-30621 were dosed via nose-only inhalation five days a week, for sixteen weeks, while Zileuton was administered orally. Dose levels for S-29606 and S-30621 were determined to be 220 µg/kg and 430 µg/kg for the low and high dose groups, respectively, while the dose of Zileuton was 245 mg/kg. Both test compounds exhibited a significant reduction of pulmonary adenomas, compared to 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 to 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.

Keywords: Chemoprevention; A/J mouse; Lipoxygenase; Inhalation; Lung.
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