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[Cancer Research 62, 4199-4201, August 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Chemoprevention by Lipoxygenase and Leukotriene Pathway Inhibitors of Vinyl Carbamate-induced Lung Tumors in Mice1

William T. Gunning2, Paula M. Kramer, Vernon E. Steele and Michael A. Pereira

Department of Pathology, Medical College of Ohio, Toledo, Ohio 43614 [W. T. G., P. M. K., M. A. P.], and Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892 [V. E. S.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Conclusions
 REFERENCES
 
5-Leukotriene pathway inhibitors, Accolate, MK-886, and Zileuton, were evaluated as chemopreventive agents in female strain A mice. The mice were administered by injection vinyl carbamate (2 x 16 mg/kg) to induce lung tumors. Two weeks later, they received in their diet Accolate (270 and 540 mg/kg), MK-886 (30 mg/kg), Zileuton (600 and 1200 mg/kg), or combinations containing the lower concentration of two agents. Thirteen weeks later, Accolate, Zileuton (only the high concentration), and combinations of Zileuton with either Accolate or MK-886 reduced lung tumor multiplicity. At week 43, MK-886, Accolate, and Zileuton reduced lung tumor multiplicity by 37.8, 29.5, and 28.1%, respectively. They also decreased the size of the tumors and the yield of carcinomas. These results demonstrate that leukotriene inhibitors prevent lung tumors and slow the growth and progression of adenomas to carcinoma; leukotriene inhibitors warrant further consideration for potential use in humans.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Conclusions
 REFERENCES
 
The purpose of this study was to evaluate the efficacy of three 5-leukotriene pathway inhibitors (Accolate, MK-886, and Zileuton) to prevent lung tumors in mice. The potential use of leukotriene inhibitors for cancer prevention has been reviewed recently (1) . Inhibitors of the 5-lipoxygenase pathway have been reported to prevent lung cancer in mice and to slow the growth of lung cancer cells (1, 2, 3, 4) . The lipoxygenase inhibitor, A-79175, and the inhibitor of 5-lipoxygenase-activating protein, MK-886, were reported to reduce the multiplicity of NNK3 -induced lung tumors and to reduce the mean tumor volume (2) . Furthermore, the combination of A-79175 with the cyclooxygenase inhibitor, acetylsalicylic acid, was more efficacious in reducing the multiplicity of lung tumors than either drug administered alone.

Accolate (Zafirlukast; cyclopentyl 3-[2-methoxy-4-{[o-tolylsulfonyl]benzyl}-1-methylindole-5-carbamate), MK-886, and Zileuton [N-(1-benzo[b]-thien-2yl)ethyl)-N-hydroxyurea] were chosen for study because they affect the lipoxygenase pathway by different mechanisms. Accolate is a peptidyl leukotriene antagonist and inhibitor of LTD4 (5) , MK-886 is a 5-lipoxygenase-activating protein inhibitor that binds to the arachidonic acid binding site (6) , and Zileuton is a N-hydroxyurea inhibitor of 5-lipoxygenase (7) . Furthermore, their ability to inhibit different steps in the pathway might allow for additive or synergistic inhibitory activity if combinations of lipoxygenase inhibitors are used to inhibit lung tumor formation.

The strain A mouse lung tumor model is the most widely used animal model to study both lung carcinogenesis and chemoprevention (8 , 9) . To evaluate drugs for chemoprevention in this model, lung tumors have been induced by benzo(a)pyrene, NNK, urethane, or vinyl carbamate (9) . Vinyl carbamate was chosen to induce the lung tumors in our study because among these carcinogens, it induced the greatest yield of carcinomas, i.e., ~40% of the tumors at 1 year (10) . Also among these carcinogens, vinyl carbamate induced the greater yield of lung tumors (11) . We administered the leukotriene inhibitors starting 2 weeks after the last dose of vinyl carbamate to evaluate their effect during the promotional phase of carcinogenesis. Hence, the leukotriene inhibitors were evaluated for chemopreventive efficacy independent of an effect on the uptake, metabolism, and distribution of vinyl carbamate.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Conclusions
 REFERENCES
 
Chemicals.
Vinyl carbamate (purity >99%) was purchased from Toronto Research Chemicals (North York, Ontario, Canada). MK-886 was acquired from the DCPC Repository (c/o McKesson Bioservices, Rockville, MD). Accolate as 20-mg tablets (lot FAD721) was from Zeneca Pharmaceuticals (Wilmingham, DE). Zileuton as 600-mg Zyflo tablets (lot 52019AF21) was from Abbott Laboratories (North Chicago, IL).

Animals.
Female A/J mice (5–6 weeks of age) were purchased from The Jackson Laboratory (Bar Harbor, ME). The mice were housed in our American Association of Laboratory Animal Care-accredited laboratory animal facility. Mice were housed in polycarbonate solid-bottom, shoebox-type cages (height, 13 cm; width, 18 cm; length, 28 cm) with Anderson Bed-o-Cob 1/8 bedding (Anderson’s, Maumee, OH). The mice were quarantined for 2 weeks before the bioassay. The environment in the animal rooms was maintained at a temperature of 72 ± 2°F, relative humidity of 40–60%, at least 10–15 air changes/h, ~30 foot candles of light (cage level), and a light cycle of 12 h on/12 h off. The diet was a semipurified AIN-76A (modified) containing 20% casein, 0.3% DL-methionine, 52% cornstarch, 13% dextrose, 5% corn oil, 5% Alphacel fiber, 3.5% AIN mineral mixture, 1.0% AIN vitamin mixture, and 0.2% choline bitartrate (Dyets, Inc., Bethlehem, PA). The leukotriene inhibitors were mixed into the AIN-76A diet. The diet and drinking water were provided ad libitum.

When the mice were 7–8 weeks of age, they were administered the first of two i.p. injections of vinyl carbamate of 16 mg/kg each and 7 days apart. Two weeks after the second dose of vinyl carbamate, the mice received the leukotriene inhibitors in their diet. Accolate (270 or 540 mg/kg), Zileuton (600 or 1200 mg/kg), and MK-886 (30 mg/kg) was provided at the indicated mg/kg concentrations in the diet. The doses selected for this study were based upon reports published previously (2 , 3 , 12) ; the high dose of Accolate was ~100 times the Food and Drug Administration-approved dose for humans to counteract decreased bioavailability when provided in the animal diet. Binary combinations containing 600 mg/kg Zileuton with 270 mg/kg Accolate or 30 mg/kg MK-886 and 270 mg/kg Accolate with 30 mg/kg MK-886 were also provided. Mice were weighed weekly through the first 6 weeks of exposure to the leukotriene inhibitors. After which, they were then weighed every 2–4 weeks until sacrificed. Mice were sacrificed by carbon dioxide asphyxiation after 13 and 43 weeks of exposure to the drugs. The lungs were harvested, fixed overnight in formalin, transferred to 70% alcohol, and evaluated for tumors before embedding in paraffin for histology.

Histopathological Evaluation.
Lung tumors were classified as being solid/alveolar adenomas, papillary adenomas, and undifferentiated carcinomas. The criteria used for solid/alveolar adenoma classification required well-differentiated, cuboidal-shaped cells obliterating at least three contiguous alveolar spaces (13) . Papillary tumors were identified as well-differentiated columnar cells with pleomorphic nuclei expanding within the lung parenchyma as finger-like projections. Carcinomas were classified by identifying populations of large undifferentiated cells with an increased nuclear:cytoplasmic ratio, large pleomorphic nuclei, and with complete loss of normal alveolar architecture.

Statistical Analysis.
Results are presented as mean ± SE. They were analyzed by an ANOVA followed by a Tukey test with significance indicated by P < 0.05.


   Results and Conclusions
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Conclusions
REFERENCES
 
The dose levels of the three leukotriene inhibitors and of the combinations were not toxic. Reported adverse effects in humans for the two Food and Drug Administration-approved drugs (Accolate and Zileuton) are potential elevations of liver enzymes and hypersensitivity reactions to the drugs or their active ingredients. Although Phase I human trials were discontinued for lack of efficacy in asthmatics, adverse effects of MK866 in humans have not been reported. During the course of the study, the mice did not exhibit any clinical sign of toxicity, nor were body weight gains affected by treatment. In fact, mice administered Accolate and MK-886 gained more weight than mice administered the control diet (data not shown). Also, none of the leukotriene inhibitors or their combinations altered the liver or spleen:body weight ratios.

The ability of the leukotriene inhibitors to prevent vinyl carbamate-induced lung tumors is presented in Table 1Citation . After 13 weeks of exposure, the yield of lung tumors was significantly decreased by both dose levels of Accolate (270 and 540 mg/kg), the high dose of Zileuton (1200 mg/kg), and the combinations containing 600 mg/kg Zileuton with either Accolate or MK-866. The efficacy of the combination containing Zileuton and Accolate to prevent lung tumors was not significantly different from the efficacy of either inhibitor administered alone. Although when administered alone at the dose level in their combination, neither Zileuton or MK-886 prevented lung tumors; the combination containing them did significantly prevent tumors. In contrast, the combination containing Accolate and MK-886 did not reduce the yield of tumors, whereas Accolate administered alone did significantly reduce the yield of tumors.


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  		Table 1 Yield of vinyl carbamate-induced lung tumors

 
After 13 weeks of drug exposure, the results from the mice demonstrated that two leukotriene inhibitors, Accolate and Zilueton, when administered starting 2 weeks after vinyl carbamate were capable of preventing lung tumors during the promotional phase of carcinogenesis. Two of the three binary combinations of the leukotriene inhibitors also demonstrated the ability to prevent lung tumors. However, the binary combinations did not demonstrate a consistent advantage for using more than one agent. The combination of Zilueton and Accolate was no more efficacious than either agent alone, of Zilueton and MK-886 was more efficacious than either agent, and of Accolate and MK-886 was less efficacious than one of the agents (Accolate). With the exception of MK-886, there was no significant difference between the various chemopreventive agent treatment groups regarding efficacy of lung tumor inhibition.

After 43 weeks of drug provided in the diet, all three leukotriene inhibitors significantly reduced the yield of lung tumors (Table 1)Citation . MK-866 was the most efficacious, reducing tumor yield by 37.8%, followed by Accolate (29.5%) and Zileuton (28.1%). There was no significant difference of lung tumor multiplicity between the three leukotriene inhibitor treatment groups. The leukotriene inhibitors reduced the size of the tumors (Fig. 1)Citation . The tumors were divided into the three size categories of <1, 1–3, and >3 mm. Most of the tumors, regardless of treatment, were 1–3 mm in diameter. All three lipoxygenase inhibitors decreased the number of lung tumors of this size. The histological morphology of the tumors is presented in Fig. 2Citation . The tumors were classified as being solid adenomas, papillary adenomas, or carcinomas. In mice that received the control diet, carcinomas were the most common tumor type, comprising 44% of the tumors. All three leukotriene inhibitors significantly decreased the yield of carcinomas. The yield of solid and papillary adenomas was not significantly decreased by the leukotriene inhibitors, except for solid adenomas by MK-886 and papillary adenomas by Accolate. The results demonstrate that the leukotriene inhibitors decreased the growth and progression of adenomas to carcinomas.



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  		Fig. 1. Effect of leukotriene inhibitors on the size of the lung tumors: week 43. The mice were sacrificed after 43 weeks of exposure to the leukotriene inhibitors. The tumors were divided into three size categories, <1, 1–3, and >3 mm. The results are mean with statistical significance of P < 0.05 indicated by the asterisk; bars, SE. Tumors >3 mm usually have a papillary or carcinomatous morphology.

 


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  		Fig. 2. Effect of leukotriene inhibitors on tumor morphology: week 43. H&E-stained lung tissue was evaluated for tumors that were classified as solid adenomas, papillary adenomas, or adenocarcinomas. The results are means; bars, SE. *, statistical significance difference for the tumor type in mice that received the control diet (P < 0.05).

 
Leukotriene inhibitors A-79175 and MK-886 have been shown previously to reduce the multiplicity of NNK-induced lung tumors in mice (2) . Our data demonstrate that one of these drugs, MK-886, and two other leukotriene inhibitors, Accolate and Zileuton, prevent lung tumors when administered during the promotional phase of carcinogenesis, i.e., after the carcinogen. Thus, drugs that inhibit the leukotriene pathway by three different mechanisms: (a) an inhibitor of LTD4 (Accolate); (b) a 5-lipoxygenase-activating protein inhibitor (MK-886); and (c) a 5-lipoxygenase inhibitor (Zileuton), all prevented lung tumors. Because the dose levels of the drugs that were used are comparable with human doses currently used to treat asthma, our data demonstrate that lipoxygenase inhibitors may be useful as potential cancer chemopreventive compounds, as suggested previously in the literature (12 , 14) . Combinations of these lipoxygenase inhibitors with different mechanisms did not appear to have a significantly greater chemopreventive activity than the individual drugs. Thus, our results do not support the use of combinations of leukotriene inhibitors to obtain additive or synergistic prevention of lung tumors. However, our evaluation was too limited to exclude that possibility. The ability of the leukotriene inhibitors to slow the neoplastic progression to cancer was indicated by the decrease in both the size of the tumors and the yield of carcinomas. The leukotriene inhibitors were administered starting 2 weeks after the vinyl carbamate, i.e., during the promotional phase of carcinogenesis, so that they appear to slow the progression to cancer by inhibiting this phase of carcinogenesis. Thus, it would appear warranted to further evaluate and develop leukotriene inhibitors as chemopreventive drugs for potential use in humans.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by Contract N01-CN-85146 from the National Cancer Institute. Back

2 To whom requests for reprints should be addressed, at Department of Pathology, Block Health Science Building, Medical College of Ohio, 3035 Arlington Avenue, Toledo, OH 43614-5806. Phone: (419) 383-5256; Fax: (419) 383-3066; E-mail: wgunning{at}mco.edu Back

3 The abbreviation used is: NNK, 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone. Back

Received 4/24/02. Accepted 6/13/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Conclusions
 REFERENCES
 

  1. Avis I. M., Jett M., Boyle T., Vos M. D., Moody T., Treston A. M., Martinez A., Mulshine J. L. Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling. J. Clin. Investig., 97: 806-813, 1996.[Medline]
  2. Rioux N., Castonguay A. Inhibitors of lipoxygenase: a new class of cancer chemopreventive agents. Carcinogenesis (Lond.), 19: 1393-1400, 1998.[Abstract/Free Full Text]
  3. Moody T. W., Leyton J., Martinez A., Hong S., Malkinson A., Mulshine J. L. Lipoxygenase inhibitors prevent lung carcinogenesis and inhibit non-small cell lung cancer growth. Exp. Lung Res., 24: 617-628, 1998.[Medline]
  4. Hussey H. J., Tisdale M. J. Inhibition of tumour growth by lipoxygenase inhibitors. Br. J. Cancer, 74: 683-687, 1996.[Medline]
  5. Bernstein P. R. Chemistry and structure-activity relationships of leukotriene receptor antagonists. Am. J. Respir. Crit. Care Med., 157: S220-S225, discussion S225–S226, S247–S248 1998.[Medline]
  6. Datta K., Biswal S. S., Kehrer J. P. The 5-lipoxygenase-activating protein (FLAP) inhibitor, MK886, induces apoptosis independently of FLAP. Biochem. J., 340: 371-375, 1999.
  7. Dube L. M., Swanson L. J., Awni W. Zileuton, a leukotriene synthesis inhibitor in the management of chronic asthma. Clinical pharmacokinetics and safety. Clin. Rev. Allergy Immunol., 17: 213-221, 1999.[Medline]
  8. Stoner G. D., Morse M. A., Kelloff G. J. Perspectives in cancer chemoprevention. Environ. Health Perspect., 105: 945-954, 1997.
  9. Steele V. E., Moon R. C., Lubet R. A., Grubbs C. J., Reddy B. S., Wargovich M., McCormick D. L., Pereira M. A., Crowell J. A., Bagheri D., et al Preclinical efficacy evaluation of potential chemopreventive agents in animal carcinogenesis models: methods and results from the NCI Chemoprevention Drug Development Program. J. Cell. Biochem. Suppl., 20: 32-54, 1994.[Medline]
  10. Gunning W. T., Kramer P. M., Lubet R. A., Steele V. E., Pereira M. A. Chemoprevention of vinyl carbamate-induced lung tumors in strain A mice. Exp. Lung Res., 26: 757-772, 2000.[Medline]
  11. Stoner G. D., Conran P. B., Greisiger E. A., Stober J., Morgan M., Pereira M. A. Comparison of two routes of chemical administration on the lung adenoma response in strain A/J mice. Toxicol. Appl. Pharmacol., 82: 19-31, 1986.[Medline]
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