AAPS PharmSciTech

, Volume 11, Issue 1, pp 168–173 | Cite as

Inhalation of an Ethanol-Based Zileuton Formulation Provides a Reduction of Pulmonary Adenomas in the A/J Mouse Model

  • Kelly L. Karlage
  • Erik Mogalian
  • Annikka Jensen
  • Paul B. Myrdal
Research Article

Abstract

Potential efficacy of zileuton, a 5-LOX inhibitor, was evaluated for the reduction of pulmonary adenomas in the A/J murine model when administered via nose-only inhalation. Development of pulmonary adenomas was induced with benzo(a)pyrene. Animals were treated with a zileuton solution (5 mg/mL in 85:15 ethanol/water) either twice weekly or five times a week via nose-only inhalation; The placebo solution (85:15 EtOH/H2O, no active) was also evaluated. Dose delivered was calculated to be 1.2 mg/kg per exposure for each zileuton group. After 20 weeks of treatment, surface tumors were enumerated and histologically assessed. A significant reduction in tumor count was noted for both the twice weekly administration (40%) and the five times a week administration (59%). The data also showed a significant reduction for the group, which received the placebo (approximately 58%). The treatment groups were also found to have an impact on the histological stages of adenoma development.

Key words

aerosol chemoprevention ethanol lung cancer zileuton 

Notes

Acknowledgment

This research study was funded by the Arizona Biomedical Research Commission, Grant no. 5-082.

References

  1. 1.
    American Cancer Society. Cancer Reference Information [Internet]. c2009 [cited 2009 Jun 8]. http://www.cancer.org/docroot/CRI/content.
  2. 2.
    Gupta PK. Drug targeting in cancer chemotherapy: a clinical perspective. J Pharm Sci. 1990;79(11):949–62.CrossRefPubMedGoogle Scholar
  3. 3.
    Gagnadoux F, Hureaux J, Vecellio L, Urban T, Le Pape A, Valo I, et al. Aerosolized chemotherapy. J Aerosol Med. 2008;21(1):1–9.Google Scholar
  4. 4.
    Rioux N, Castonguay A. Inhibitors of lipoxygenase: a new class of cancer chemopreventives agents. Carcinogenesis. 1998;19(8):1393–400.CrossRefPubMedGoogle Scholar
  5. 5.
    Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubert RA, Crowell JA, et al. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev. 1999;8(5):467–83.PubMedGoogle Scholar
  6. 6.
    Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubert RA, Crowell JA, et al. Potential use of lipoxygenase inhibitors for cancer chemoprevention. Exp Opin Invest Drugs. 2000;9:2121–38.CrossRefGoogle Scholar
  7. 7.
    Moody TW, Leyton J, Martinez A, Hong S, Malkinson A, Mulshine JL. Lipoxygenase inhibitors prevent lung carcinogenesis and inhibit non-small cell cancer growth. Exp Lung Res. 1998;24:617–62.CrossRefPubMedGoogle Scholar
  8. 8.
    Avis IM, Jett M, Boyle T, Vos MD, Moody T, Treston AM, et al. Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling. J Clin Inv. 1996;97(3):806–13.CrossRefGoogle Scholar
  9. 9.
    Bell RL, Young PR, Albert D, Lanni C, Summers JB, Brooks DW, et al. The discovery and development of Zileuton: an orally active 5-lipoxygenase inhibitor. Int J Immunopharmac. 1992;14(3):505–10.CrossRefGoogle Scholar
  10. 10.
    Carter GW, Young PR, Albert DH, Bouska J, Dyer R, Bell RL, et al. 5-Lipoxygenase inhibitory activity of Zileuton. J Pharm Exp Thera. 1991;256(3):929–37.Google Scholar
  11. 11.
    Gunning WT, Kramer PM, Steele VE, Pereira MA. Chemoprevention by lipoxygenase and leukotriene pathway inhibitors of vinyl carbamate-induced lung tumors in mice. Cancer Res. 2002;62:4199–201.PubMedGoogle Scholar
  12. 12.
    Myrdal PB, Karlage K, Kuehl PJ, Angersbach BS, Merrill BA, Wightman PD. Effects of novel 5-lipoxygenase inhibitors on the incidence of pulmonary adenomas in the A/J murine model when administered via nose only inhalation. Carcinogenesis. 2007;28(5):957–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Estensen RD, Jordan MM, Wiedmann TS, Galbraith AR, Steele VE, Wattenberg LW. Effect of chemopreventive agents on separate stages of progression of benzo(a)pyrene induced lung tumors in A/J mice. Carcinogenesis. 2004;25(2):197–201.CrossRefPubMedGoogle Scholar
  14. 14.
    Stein SW, Myrdal PB, Gabrio BJ, Obereit D, Beck TJ. Evaluation of a new aerodynamic particle sizer spectrometer for size distribution measurement of solution metered dose inhalers. J Aerosol Med. 2003;16(2):107–19.CrossRefPubMedGoogle Scholar
  15. 15.
    Wattenberg LW, Wiedmann TS, Zimmerman CL, Galbraith AR, Steele VE, Kelloff GJ. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone diproprionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis. 2000;21:179–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Alexander DJ, Collins CJ, Coombs DW, Gilkison IS, Hardy CJ, Healey G, et al. Association of inhalation toxicologists (AIT) working party recommendation for standards delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals. Inhal Toxicol. 2008;20:1179–89.CrossRefPubMedGoogle Scholar
  17. 17.
    Foley JF, Anderson MW, Stoner GD, Gaul BW, Hardsity JF, Maronpot RR. Proliferative lesions of the mouse lung: progression studies in strain A mice. Exp Lung Res. 1991;17:157–68.CrossRefPubMedGoogle Scholar
  18. 18.
    Dungworth DL, Rittinghausen S, Schwartz L, Harkema JR, Hayashi Y, Killel B, et al. Respiratory system and mesothelium. In: Mohr U, editor. International classification of rodent tumors: the mouse. Germany: Springer; 2001. p. 87–138.Google Scholar
  19. 19.
    Garro AJ, Lieber CS. Alcohol and cancer. Annu Rev Pharmacol Toxicol. 1990;30:219–49.CrossRefPubMedGoogle Scholar
  20. 20.
    Seitz HK, Simanowski UA. Alcohol and carcinogenesis. Am Rev Nutr. 1988;8:99–119.CrossRefGoogle Scholar
  21. 21.
    Yirmiya R, Ben-Eliyahu S, Gale RP, Shavit Y, Liebeskind JC, Taylor AN. Ethanol increases tumor progression in rats: possible involvement of natural killer cells. Brain Behav Immun. 1992;6:74–86.CrossRefPubMedGoogle Scholar
  22. 22.
    Nachiappan V, Mufti SJ, Chakravarti A, Eskelson CD. Rajacekharan. Lipid peroxidation and ethanol-related tumor promotion in Fisher-344 rats treated with tobacco-specific nitrosamines. Alcohol Alcohol. 1994;29(5):565–74.PubMedGoogle Scholar
  23. 23.
    Wu W-J, Pruett SB. Ethanol decreases host resistance to pulmonary metastases in a mouse model: role of natural killer cells and ethanol-induced stress response. Int J Cancer. 1999;82:886–92.CrossRefPubMedGoogle Scholar
  24. 24.
    Beland FA, Benson RW, Mellic PW, Kovatch RM, Roberts DW, Fang J-L, et al. Effect of ethanol on the tumorigenicity of urethane (ethyl carbamate) in B6C3F1 mice. Food Chem Toxicol. 2005;43:1–19.CrossRefPubMedGoogle Scholar
  25. 25.
    Altmann H-J, Dusemond B, Goll M, Grunow W. Effect of ethanol on the induction of lung tumors by ethyl carbamate in mice. Toxicology. 2005;43:1–19.Google Scholar
  26. 26.
    Djousee L, Dorgan JF, Zhang Y, Schatzkin A, Hood M, D’Agostino RB, et al. Alcohol consumption and risk of lung cancer: the Framingham study. J Natl Cancer Inst. 2002;94(24):1877–82.Google Scholar
  27. 27.
    Zang EA, Wynder EL. Reevaluation of the confounding effect of cigarette smoking on the relationship between alcohol use and lung cancer risk with larynx cancer used as a positive control. Prev Med. 2001;32:359–70.CrossRefPubMedGoogle Scholar
  28. 28.
    Dahl AR, Grossi IM, Houchens DP, Scovell LJ, Placek ME, Imondi AR, et al. Inhaled isotrenoin (13-cis retinoic acid) is an effective lung cancer chemopreventive agent in A/J mice at low doses: a pilot study. Clin Cancer Res. 2000;6:3015–24.PubMedGoogle Scholar
  29. 29.
    Stoewsand GS, Anderson JL, Munson L. The role of wine in ethyl carbamate induced carcinogenesis inhibition. ACS Symposium Series. 1997;661:220–36.Google Scholar
  30. 30.
    Kristiansen E, Clemmensen S, Meyer O. Chronic ethanol intake and reduction of lung tumors from urethane in strain A mice. Fd Chem Toxic. 1990;28(1):35–8.CrossRefGoogle Scholar
  31. 31.
    Batkin S, Tabrah FL. Ethanol vapour modulation of Lewis lung carcinoma, a murine pulmonary tumour. J Cancer Res Clin Oncol. 1990;116:187–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Yum S, Lee E, Taskovich L, Theeuwes F. Permeation enhancement with ethanol: mechanism of action through the skin. Drugs Pharmaceut Sci. 1994;62:143–70.Google Scholar
  33. 33.
    Gupta A, Stein SW, Myrdal PB. Balancing ethanol cosolvent concentration with product performance in 134a-based pressurized metered dose inhalers. J Aerosol Med. 2003;16(2):167–74.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  • Kelly L. Karlage
    • 1
  • Erik Mogalian
    • 2
  • Annikka Jensen
    • 1
  • Paul B. Myrdal
    • 1
  1. 1.College of PharmacyUniversity of ArizonaTucsonUSA
  2. 2.Gilead Sciences, IncFoster CityUSA

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