Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a γ-dominant PPAR α/γ agonist: Lack of evidence for urolithiasis as an inciting event

Toxicologic Pathology

Volumn 36, Issue 2, 2008, Pages 218-231

  Long, Gerald G ^a   Reynolds, Vincent L ^a   Lopez Martinez, Alric ^b   Ryan, Thomas E ^b   White, Sandy L ^a   Eldridge, Sandra R ^c  

^a ELI LILLY AND COMPANY   (United States)

^b 206 Carnegie Center   (United States)

^c CHARLES RIVER LABORATORIES   (United States)

Author keywords

Carcinogenesis; PPAR agonist; Rats; Urinary bladder; Urolithiasis; Urothelium

Indexed keywords

CYTOKERATIN 20; NAVEGLITAZAR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBODY LABELING; ARTICLE; BLADDER; BLADDER CARCINOGENESIS; CANCER THERAPY; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL STRUCTURE; CIRCADIAN RHYTHM; CONTROLLED STUDY; DISEASE ASSOCIATION; DRUG DOSAGE FORM COMPARISON; FEMALE; HYPERPLASIA; MITOGENESIS; NONHUMAN; PRIORITY JOURNAL; RAT; SEX DIFFERENCE; STATISTICAL SIGNIFICANCE; URINALYSIS; URINE PH; URINE SEDIMENT; UROLITHIASIS; UROTHELIUM;

ANIMALS; CALCIUM; CARCINOGENICITY TESTS; CELL PROLIFERATION; CRYSTALLIZATION; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HYPERPLASIA; LONGEVITY; MALE; PHENYLPROPIONATES; PPAR GAMMA; RATS; RATS, INBRED F344; URINALYSIS; URINARY BLADDER; URINARY BLADDER NEOPLASMS; UROLITHIASIS; UROTHELIUM;

RATTUS;

EID: 42249084078     PISSN: 01926233     EISSN: 15331601     Source Type: Journal    
DOI: 10.1177/0192623307311757     Document Type: Article

References (49)

1. Berger, J., and Moller, D.E. (2002). The mechanisms of action of PPARs. Annu Rev Med 53, 409-35.
2. Cheng, J., Huang, H., Zhang, Z.T., Shapiro, E., Pellicer, A., Sun, T.T., and Wu, X.R. (2002). Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth. Cancer Res 62, 4157-63.
3. Clayson, D.B., Fishbein, L., and Cohen, S.M. (1995). Effects of stones and other physical factors on the induction of rodent bladder cancer. Fd Chem Toxicol 9, 771-84.
4. Cohen, S.M. (2005). Effects of PPARγ and combined agonists on the urinary tract of rats and other species. Toxicol Sci 87, 322-7.
5. Cohen, S.M., Cano, M., Johnson, L.S., St-John, M.K., Asamoto, M., Garland, E.M., Thyssen, J.H., Sangha, G.K., and Van Goethem, D.L. (1994). Mitogenic effects of propoxur on male rat bladder urothelium. Carcinogenesis 15, 2593-7.
6. Cohen, S.M., Johansson, S.L., Arnold, L.L., and Lawson, T.A. (2002). Urinary tract calculi and thresholds in carcinogenesis. Food Chem Toxicol 40, 793-9.
7. Cohen, S.M., Ohnishi, T., Clark, N.M., He, J., and Arnold, L.L. (2007). Investigations of rodent urinary bladder carcinogens: collection, processing, and evaluation of urine and bladders. Toxicol Pathol 35, 337-47.
8. Dominick, M.A., White, M.R., Sanderson, T.P., Van Vleet, T. Cohen, S.M., Arnold, L.E., Cano, M., Tannehill-Gregg, S., Moehlenkamp, J.D., Waites, C.R., and Schilling, B.E. (2006). Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR α/γ agonist: evidence for urolithiasis as the inciting event in the mode of action. Toxicol Pathol 34, 903-20.
9. Egerod, F.L., Nielsen, H.S., Iversen, L., Thorup, I., Storgaard, T., and Oleksiewicz, M.B. (2005). Biomarkers for early effects of carcinogenic dual-acting PPAR agonists in rat urinary bladder urothelium in vivo. Biomarkers 10, 295-309.
10. Eldridge, S.R., Tilbury, L.F., Goldsworthy, T.L., and Butterworth, B.E. (1990). Measurement of chemically induced cell proliferation in rodent liver and kidney: a comparison of 5-bromo-2'-deoxyuridine and [3H]thymidine administered by injection or osmotic pump. Carcinogenesis 11, 2245-51.
11. El Hage, J.E. (2005 a). Peroxisome proliferator-activated receptor agonists: carcinogenicity findings and regulatory recommendations. 3rd International Symposium on PPARs Efficacy and Safety, Monoco, March 19-23, 2005.
12. El Hage, J. (2005 b). Toxicity profiles of peroxisome proliferator-activated receptor (PPAR) agonists and preclinical safety profile for muraglitazar. http://www.fda.gov/ohms/dockets/ac/05/slides/2005- 4169S2_02_02-FDA-ElHage_files/frame.htm.
13. Fauconnet, S., Lascombe, I., Chabannes, E., Adessi, G.L., Desvergne, B., Wahli, W., Bittard, H. (2002). Differential regulation of vascular endothelial growth factor expression by peroxisome proliferator-activated receptors in bladder cancer cells. J Biol Chem 28, 23534-43.
14. Frith, C.H., Fukushima, S., Cohen, S.M., Squire, R.A., and Chandra, M. (1995). Proliferative lesions of the lower urinary tract in rats. URG-2. In: Guides for Toxicologic Pathology. STP/ARP/AFIP, Washington, DC.
15. Gardner, O.S., Dewar, B.J., Earp, H.S., Samet, J.M., and Graves, L.M. (2003). Dependence of peroxisome proliferator-activated receptor ligand-induced mitogen-activated protein kinase signaling on epidermal growth factor receptor transactivation. J Boil Chem 47, 46261-9.
16. Goodman, D.G., Ward, J.M., Squire, R.A., Chu, K.C., and Linhart, M.S. (1979). Neoplastic and nonneoplastic lesions in aging F344 rats. Toxicol App Pharmacol 48, 237-48.
17. Grommes, C., Landreth, G.E., and Heneka, M.T. (2004). Antineoplastic effects of peroxisome proliferators-activated receptor gamma agonists. Lancet Oncol 5, 419-29.
18. Guan, Y., Zhang, Y., Davis, L., and Breyer, M.D. (1997). Expression of peroxisome proliferators-activated receptors in urinary tract of rabbits and humans. Am J Physiol 273, F1013-22.
19. Harnden, P., Allam, A., Joyce, A., Patel, A., Selby, P., and Southgate, J. (1995). Cytokeratin 20 expression by non-invasive transitional cell carcinomas: potential for distinguishing recurrent from non-recurrent disease. Histopathol 27, 169-74.
20. Harnden, P., Eardley, I., Joyce, A.D., and Southgate, J. (1996). Cytokeratin 20 as an objective marker of urothelial dysplasia. Br J Urol 78, 870-5.
21. Harnden, P., Mahmood, N., and Southgate, J. (1999). Expression of cytokeratin 20 redefines urothelial papillomas of the bladder. Lancet 353, 974-7.
22. Haseman, J.K., Arnold, J., and Eustis, S.L. (1990). Tumor incidences in Fischer 344 rats: NTP historical data. In Pathology of the Fischer Rat (G. A. Boorman, S. L. Eustis, R. R. Elwell, C. A. Montgomery Jr., and W. F. MacKenzie, eds., pp. 355-65). Academic Press, San Diego, CA.
23. Kawakami, S., Arai, G., Hayashi, T., Fujii, Y., Xia, G., Kageyama, Y., and Kihara, K. (2002). PPARγ ligand suppress proliferation of human urothelial basal cells in vitro. J Cell Physiol 191, 310-9.
24. Lefebvre, A-M., Chen, I., Desreumaux, P., Najib, J., Fruchart, J-C., Geboes, K., Briggs, M., Heyman, R., and Auwerx, J. (1998). Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+mice. Nature Med 4, 1053-7.
25. Lin, K.K. (1997). Guidance for industry: statistical aspects of design, analysis, and interpretation of animal carcinogenicity studies. Draft guidelines. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD.
26. Lin, K.K., and Rahman, M.A. (1998). Overall false positive rates in tests for linear trend in tumor incidences in animal carcinogenicity studies of new drugs. J Biopharm Stats 8, 1-15.
27. Martin, B.F. (1972). Cell replacement and differentiation in transitional epithelium, a histological and autoradiographic study of the guinea-pig bladder and ureter. J Anat 112, 433-66.
28. Messing, E.M. (1992). Growth factors and bladder cancer: clinical implications of the interactions between growth factors and their urothelial receptors. Seminar Surg Oncol 8, 285-92.
29. Messing, E.M., Hanson, P., Ulrich, P., and Erturk, E. (1987). Epidermal growth factor-interactions with normal and malignant urothelium: in vivo and in situ studies. J Urol 138, 1329-35.
30. Molon-Noblot, S., Boussiquet-Leroux, C., Owen, R.A., Irisarri, E., Durand-Cavagna, G., Peter, C.P., and Duprat, P. (1992). Rat urinary bladder hyperplasia induced by oral administration of carbonic anhydrase inhibitors. Toxicol Pathol 20, 93-102.
31. Monticello, T.M., Morgan, K.T., and Hurtt, M.E. (1990). Unit length as the denominator for quantitation of cell proliferation in nasal epithelia. Toxicol Pathol 18, 24-31.
32. Nakashiro, K., Hayashi, Y., Kita, A., Tamatani, T., Chienski, A., Usuda, N., Hattori, K., Reddy, J.K., and Oyasu, R. (2001). Role of peroxisome proliferator-activated receptor-γ and its ligands in non-neoplastic and neoplastic human urothelial cells. Am J Pathol 159, 591-7.
33. Oleksiewicz, M.B., Thorup, I., Henriette, S.N., Hanne, V.A., Hegelund, A.C., Iversen, L., Guldberg, T.S., Brinck, P.R., Sjogren, I., Thinggaard, U.K., Jørgensen, L., and Jensen, M.B. (2005). Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo. Toxicol Pathol 33, 552-60.
34. Osborne, C.A., Davis, L.S., Sanna, J., Unger, L.K., O'Brien, T.D., Clinton, C.W., and Davenport, M.P. (1990). Identification and interpretation of crystalluria in domestic animals: a light and scanning microscopic study. Vet Med 85, 18-37.
35. Possati, L., Rocchetti, R., Talevi, S., Beatrici, V., Margiotta, C., Ferrante, L., Calza, R., Sagrini, D., and Ferri, A. (2002). The role of peroxisome proliferator-activated receptor γ in bladder cancer in relation to angiogenesis and progression. Gen Pharmacol 35, 269-75.
36. Reese, D.H., and Friedman, R.D. (1978). Suppression of dysplasia and hyperplasia by calcium in organ-cultured urinary bladder epithelium. Cancer Res 38, 586-92.
37. Reifel-Miller, A., Warshawsky, A., Ardecky, R., Baker, T., Briere, D., Brooks, D., Fraser, J., Hawkins, E., Jett, D., Klausing, K., Liu, S., Misener, E., Ogilvie, K., Rafizadeh-Montrose, C., Rizzo, J., Rungta, D., Zink, T., Zhang, T., and Brozinick J. (2003). LY519818: a novel non-TZD, PPARγdominant agonist with improved insulin sensitization and unique co-factor recruitment and response element activation profiles. Diabetes 62, A143.
38. Romih, R., Jezernik, K., and Masera, A. (1998). Uroplakins and cytokeratins in the regenerating rat urothelium after sodium saccharin treatment. Histochem Cell Biol 109, 263-9.
39. Saez, E., Tontonoz, P., Nelson, M., Alvarez, J. G. A., U. T. M., Baird, S.M., Thomazy, V.A., and Evans, R.M. (1998). Activators of the nuclear receptor PPAR γ enhance colon polyp formation. Nature Med 4, 1058-61.
40. Sarraf, P., Mueller, E., Jones, D., King, F.J., DeAngelo, D.J., Partridge, J.B., Holden, S.A., Chen, L.B., Singer, S., Fletcher, C., and Spiegelman, B.M. (1998). Differentiation and reversal of malignant changes in colon cancer through PPAR γ. Nature Med 4, 1046-52.
41. Sarraf, P., Mueller, E., Smith, W.M., Wright, H.M., Kum, J.B., Aaltonen, L.A., de la Chapelle, A., Spiegelman, B.M., and Eng, C. (1999). Loss-of-function mutations in PPAR γ associated with human colon cancer. Mol Cell 3, 799-804.
42. Spencer, P.A., Older, J.C.H., Cairns, W.J., and Southgate J. (2004). Peroxisome proliferator-activated receptor γ agonists cause cytostatsis and apoptosis in normal and neoplastic human urothelial cell lines in vitro. BJU Int 94, 1160.
43. Stahlschmidt, J., Varley, C.L., Toogood, G., Selby, P.H., and Southgate, J. (2005). Urothelial differentiation in chronically urine-deprived bladders of patients with end-stage renal disease. Kidney Int 68, 1032-40.
44. Tannehill-Gregg, S.H., Cano, M., Tomlinson, L., Cohen, S.M., Sanderson, T.P., Schilling, B.E., and Dominick, M.A. (2006). Preliminary evidence of urolithiasis with muraglitazar-related urinary bladder carcinogenesis in male rats. The Toxicologist 90, 428.
45. Varley, C.L., Stahlschmidt, J., Lee, W.C., Holder, J., Diggle, C., Selby, P.J., Trejdosiewicz, L.K., and Southgate, J. (2003). Role of PPAR and EGFR signaling in the urothelial terminal differentiation programme. Journal of Cell Science 117, 2029-36.
46. Varley, C.L., Stahlschmidt, J., Smith, B., Stower, M., and Southgate, J. (2004). Activation of peroxisome proliferator-activated receptor-γ reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells. Am J Pathol 164, 1789-98.
47. Verani, P., Romih, R., and Jezernik, K. (2004). What determines differentiation of umbrella cells. Eur J Cell Biol 83, 27-34.
48. Yoshimura, R., Matsuyama, M., Hase, T., Tsuchida, K., Kuratsukuri, K., Kawahito, Y., Sano, H., Segawa, Y., and Nakatani, T. (2003). The effect of peroxisome proliferators-activated receptor-y Ligand on urological cancer cells. Int J Molec Med 12, 861-5.
49. Yoshimura, R., Matsuyama, M., Segawa, Y., Hase, T., Mitsuhashi, M., Tsuchida, K., Wada, S., Kawahito, Y., Sano, H., and Nakatani, T. (2003). Expression of peroxisome proliferator-activated receptors (PPARs) in human urinary bladder carcinoma and growth inhibition by its agonists. Int J Cancer 104, 597-602.