Neoplastic and Non-neoplastic changes in f-344 rats treated with naveglitazar, a γ-dominant PPAR α/γ agonist

Toxicologic Pathology

Volumn 37, Issue 6, 2009, Pages 741-753

  Long, G Gerald ^a   Reynolds, Vincent L ^a   Dochterman, L Wayne ^b   Ryan, Thomas E ^b  

^a ELI LILLY AND COMPANY   (United States)

^b 206 Carnegie Center   (United States)

Author keywords

Adipose tissue; Carcinogenesis; Cardiac degeneration; Ppar agonist; Rats; Sarcoma

Indexed keywords

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

ADVERSE OUTCOME; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLADDER TUMOR; BREAST HYPERPLASIA; BREAST TUMOR; BROWN ADIPOSE TISSUE; CANCER INCIDENCE; CARDIOTOXICITY; CAUSE OF DEATH; CHRONIC KIDNEY DISEASE; CONTROLLED STUDY; CYTOPLASM VESICLE; DISEASE ASSOCIATION; DISEASE COURSE; DISEASE SEVERITY; DOSE RESPONSE; DRUG CARCINOGENICITY; DRUG MEGADOSE; FEMALE; FIBROSARCOMA; FIBROSIS; FISCHER 344 RAT; HEART INJURY; HEART MUSCLE; HEART VENTRICLE HYPERTROPHY; HISTOLOGY; LIPOSARCOMA; MALE; MESENCHYME CELL; MORNING DOSAGE; MORTALITY; MUSCLE ATROPHY; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; RAT; SARCOMA; STROMA CELL; SUBCUTANEOUS TISSUE TUMOR; TISSUE EXPANSION; WHITE ADIPOSE TISSUE;

ADIPOSE TISSUE; ANALYSIS OF VARIANCE; ANIMALS; BODY WEIGHT; CARCINOGENICITY TESTS; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; GENITALIA; HISTOCYTOCHEMISTRY; HYPERPLASIA; MALE; NEOPLASMS, EXPERIMENTAL; PHENYLPROPIONATES; PPAR ALPHA; PPAR GAMMA; RATS; RATS, INBRED F344; SARCOMA; UROTHELIUM;

RATTUS;

EID: 70649113652     PISSN: 01926233     EISSN: 15331601     Source Type: Journal    
DOI: 10.1177/0192623309343775     Document Type: Article

References (64)

1. Arakawa, K., Ishihara, T., Aoto, M., Inamasu, M., Kitamura, K., and Saito, A. (2004). An antidiabetic thiazolidinedione induces eccentric cardiac hypertrophy by cardiac volume overload in rats. Clin Exper Pharmacol Physiol 31, 8-13.
2. Berger, J., and Moller, D. E. (2002). The mechanisms of action of PPARs. Annu Rev Med 53, 409-35.
3. Braissart, O. F., Foufelle, C., Scotto, M., Dauca, M., and Whali, W. (1996). Differential expression of peroxisomal proliferator-activated receptors (PPARs) : tissue distribution of PPAR-α', -β, and-γ in the adult rats. Endocrinology 137, 354-66.
4. Buckingham, R. E., Al-Barazanji, K. A., Toseland, C. D. N., Slaughter, M., Connor, S. C., West, A., Bond, B., Turner, N. C., and Clapham, J. C. (1998). Peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47, 1326-34.
5. 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.
6. Cocchia, D., Lauriola, L., Stolfi, V. M., Tallini, G., and Michetti, F. (1983). S-100 antigen labels neoplastic cells in liposarcoma and cartilaginous tumours. Virchow's Arch 402, 139-45.
7. 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, 793-99.
8. Cohen, S. M. (2005). Effects of PPARγ and combined agonists on the urinary tract of rats and other species. Toxicol Sci 87, 322-27.
9. de Souza, C. J., Eckhardt, M., Gagen, K., Dong, M., Chen, W., Laurent, D., and Burkey, B. F. (2001). Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 50, 1863-71.
10. 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.
11. Draper, N. R., and Smith, H. (1966). Applied Regression Analysis, pp. 1-127, John Wiley and Sons, New York.
12. Dunnett, C. W. (1964). New tables for multiple comparisons with a control. Biometrics 20, 482-91.
13. rd International Symposium on PPARs Efficacy and Safety, Monaco, March 19-23, 2005.
14. El Hage, J. (2005b). Toxicity profiles of peroxisome proliferator- activated receptor (PPAR) agonists and preclinical safety profile for muraglitazar. Available at: http://www.fda.gov/ohms/dockets/ac/05/slides/2005- 4169S2-02-02-FDA-ElHage-files/frame.htm. Accessed 16 October 2005.
15. El Hage, J. (2006). Peroxisome proliferator-activated receptor (PPAR) agonists: Preclinical and clinical cardiac safety considerations. Drug Information Association Annual Meeting, Philadelphia, June 20, 2006.
16. Elstner, E., MU̧ler, C., Koshizuka, K., Williamson, E. A., Park, D., Asou, H., Shintaku, P., Said, J. W., Heber, D., and Koeffler, H. P. (1998). Ligands for peroxisome proliferator-activated receptor γ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A 95, 8806-11.
17. Fauconnet, S., Lascombe, I., Chabannes, E., Adessi, G. L., Desvergne, B., Wahli, W., and Bittard, H. (2002). Differential regulation of vascular endothelial growth factor expression by peroxisome proliferatoractivated receptors in bladder cancer cells. J Biol Chem 28, 23534-43.
18. 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, D. C.
19. 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 Appl Pharmacol 48, 237-48.
20. Greaves, P., Faccini, J. M., and Courtney C. L. (1992). Proliferative lesions in soft tissues in rats, MST-1. In: Guides for Toxicologic Pathology, STP/ARP/AFIP, Washington DC.
21. Grommes, C., Landreth, G. E., and Heneka, M. T. (2004). Antineoplastic effects of peroxisome proliferators-activated receptor gamma agonists. Lancet Oncol 5, 419-29.
22. 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.
23. Hardisty, J. F., Elwell, M. R., Ernst, H., Greaves, P., Kolenda-Roberts, H., Malarkey, D. E., Mann, P. C., and Tellier, P. A. (2007). Histopathology of hemangiosarcomas in mice and liposarcomas/fiborsarcomas in rats associated with PPAR agonists. Toxicol Pathol 35, 928-41.
24. 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, Inc., San Diego, CA.
25. Hashimoto, H., Daimaru, Y., and Enjoji, M. (1984). S-100 protein distribution in liposarcoma. An immunoperoxidase study with special reference to the distinction of liposarcoma from myxoid malignant fibrous histiocytoma. Virchow's Arch 405, 1-10.
26. Hellmold, H., Zhang, H., Anderson, U., Blomgren, B., Holland, T., Berg, A-L., Elebring, M., Sjögren, N., Bamberg, K., Dahl, B., Westerberg, R., Dillner, B., Tugwood, J., Roberts, R., Lundholm, E., Camejo, G., Skånberg, I., and Evans, J. (2007). Tesaglitazar, a PPAR a/g agonist, induces interstitial mesenchymal cell DNA synthesis and fibrosarcomas in subcutaneous tissues in rats. Toxicol Sci 98, 63-74.
27. Herman, J. R., Dethloff, L. A., McGuire, E. J., Parker, R. F., Walsh, K. M., Gough, A. W., Masuda, H., and de la Iglesia, F. A. (2002). Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone. Toxicol Sci 68, 226-36.
28. Kawakami, S., Arai, G., Hayashi, T., Fujii, Y., Xia, G., Kageyama, Y., and Kihara, K. (2002). PPARy ligand suppress proliferation of human urothelial basal cells in vitro. J Cell Physiol 191, 310-19.
29. Klaunig, J. E., Babich, M. A., Baetche, K. P., Cook, J. C., Corton, J. C., David, R. M., Deluca, J. G., Lai, D. Y., McKee, R. H., Peters, J. M., Roberts, R. A., and Fenner-Crisp, P. A. (2003). PPARα agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol 33, 655-780.
30. Kubota, T., Koshizuka, K., Willaimson, E. A., Asou, H. L., Said, J. W., Holden, S., Miyoshi, I., and Koeffler, H. P. (1998). Ligand for peroxisome proliferator-activated receptor γ (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 58, 3344-52.
31. Min/+mice. Nat Med 4, 1053-57.
32. Levene, H. (1960). Robust tests for equality of variances. In: Contributions to Probability and Statistics (I. Olkin et al. eds), pp. 278-92, Stanford University Press: Stanford, California.
33. 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.
34. 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 Stat 8, 1-15.
35. Long, G. G., Reynolds, V., Lopez, A., Ryan, T., White, S., and Eldridge, S. (2008). Characterization of changes in urinary bladders and urine parameters of rats associated with a PPAR alpha/gamma dual agonist. Toxicol Pathol 36, 218-31.
36. McConnell, E. E., Solleveld, H. A., Swenberg, J. A., and Boorman, G. A. (1986). Guidelines for combining neoplasms for evaluation of rodent carcinogenicity studies. J Nat Cancer Inst 76, 283-89.
37. Mueller, E., Sarraf, P., Tontonoz, P., Evans, R. M., Martin, K. J., Zhang, M., Fletcher, C., Singer, S., and Spegelman, B. M. (1998). Terminal differentiation of human breast cancer through PPARγ. Mol Cell 1, 465-70.
38. Na, H., and Surh, Y. (2003). Peroxisome proliferator-activated receptor γ (PPARγ) ligands as bifunctional regulators of cell proliferation. Biochem Pharmacol 66, 1381-91.
39. 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, 591-97.
40. Nesto, R. W., Bell, D., Bonow, R. O., Fonseca, V., Grundy, S. M., Horton, E. S., Le Winter, M., Porte, D., Semenkovich, C. F., Smith, S., Young, L. H., and Kahn, R. (2003). Thiazolidinedione use, fluid retention, and congestive heart failure. A consensus statement from the American Heart Association and American Diabetes Association. Circulation 108, 2941-48.
41. Okuno, A., Tamemoto, H., Tobe, K., Ueki, K., Mori, Y., Iwamoto, K., Umesono, K., Akanuma, Y., Fujiwara, T., Horikoshi, H., Yazaki, Y., and Kakowaki, T. (1998). Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 101, 1354-61.
42. Panigrahy, D., Shen, L. Q., Kieran, M. W., and Kaipainen, A. (2003). Therapeutic potential of thiazolidinediones as anticancer agents. Expert Opin Investig Drugs 12, 1925-37.
43. Peraza, M. A., Burdick A. D., Martin, H. E., Gonzalez F. J., and Peters, J. M. (2006). The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR) Toxicol Sci 90, 269-95.
44. Peto, R., Pike, M. C., and Day, N. E. (1980). "Guidelines for simple, sensitive significance tests for carcinogenic effects in long-term animal experiments, long-term and short-term screening assays for carcinogens: a critical appraisal, " IARC Monographs, Annex to Supplement 2, pp. 311-426, International Agency for Research on Cancer, Lyon, France.
45. 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, PPARγ-dominant agonist with improved insulin sensitization and unique co-factor recruitment and response element activation profiles. Diabetes 62, A143.
46. Rosen, E. D., Spiegelman, B. M. (2000). Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16, 145-71.
47. Saez, E., Tontonoz, P., Nelson, M., Alvarez, J. G., Ming, U. T., Baird, S. M., Thomazy, V. A., and Evans, R. M. (1998). Activators of the nuclear receptor PPAR γ enhance colon polyp formation. Nat Med 4, 1058-61.
48. Saez, E., Rosenfeld, J., Livolsi, A., Olson, P., Lombardo, E., Nelson, M., Banayo, E., Cardiff, R. D., Izpisua-Belmonte, J. C., and Evans, R. M. (2004). PPARγ signaling exacerbates mammary gland tumor development. Genes Dev 18, 528-40.
49. 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. Nat Med 4, 1046-52.
50. 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). Lossof-function mutations in PPAR γ associated with human colon cancer. Mol Cell 3, 799-804.
51. Spencer P. A., Older J. C. H., Cairns, W. J., and Southgate J. (2004). Peroxisome proliferator-activated receptor γ agonists cause cytostasis and apoptosis in normal and neoplastic human urothelial cell lines in vitro. BJU Int 94, 1160.
52. 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. Toxicologist 90, 428.
53. Tannehill-Gregg, S. H., Sanderson, T. P., Minnema, D., Voelker, R., Ulland, B., Cohen, S. M., Arnold, L. L., Schilling, B. E., Waites, C. R., and Dominick, M. A. (2007). Rodent carcinogenicity profile of the antidiabetic dual PPAR α and γ agonist muraglitazar. Toxicol Sci 98, 258-70.
54. Thakur, A. K. (1984). A FORTRAN program to perform the nonparametric Terpstra-Jonckheere test. Comput Programs Biomed 18, 235-40.
55. Thomas, D. G., Breslow, N., and Gart, J. J. (1977). Trend and homogeneity analyses of proportions and life table data. Comput Biomed Res 10, 373-81.
56. Tontonoz, P., Hu, E., and Spieglman, B. M. (1994). Stimulation of adipogenesis in fibroblasts by PPAR γ2, a lipid-activated transcription factor. Cell 79, 1147-56.
57. Tontonoz, P., Hu, E., and Spiegelman, B. M. (1995). Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor γ. Curr Opin Genet Dev 5, 571-76.
58. Tontonoz, P., Singer, S., Forman, B. M., Sarraf, P., Fletcher, J. A., Fletcher C. D. M., Brun, R. P., Mueller, E., Altiok, S., Oppenheim, H., Evans, R. M., Spiegelman, B. M. (1997). Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and the retinoid X receptor. Proc Natl Acad Sci U S A 94, 237-41.
59. 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 an EGFR signaling in the urothelial terminal differentiation programme. J Cell Sci 117, 2029-36.
60. 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.
61. Waites, C. R., Dominick, M. A., Sanderson, T. P., and Schiling, B. E. (2007). Nonclinical safety evaluation of muraglitazar, a novel PPAR α/gamma; agonist Toxicol Sci 100, 248-58.
62. Witner, B. J. (1971). Design and analysis of single-factor experiments. Statistical Principles in Experimental Design, Second Ed., pp. 149-260, McGraw-Hill, New York, New York.
63. +/- double mutant mice. Int J Cancer 116, 495-99.
64. 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 Mol Med 12, 861-65.