Tesaglitazar, a Dual PPAR-α/γ Agonist, Hamster Carcinogenicity, Investigative Animal and Clinical Studies

Toxicologic Pathology

Volumn 40, Issue 1, 2012, Pages 18-32

  Lindblom, Per ^a   Berg, Anna Lena ^b   Zhang, Hui ^a   Westerberg, Rolf ^b   Tugwood, Jonathan ^c   Lundgren, Hanna ^b   Marcusson Ståhl, Maritha ^b   Sjögren, Niclas ^b   Blomgren, bo ^b   Öhman, Peter ^c   Skånberg, Inger ^b   Evans, John ^c   Hellmold, Heike ^b  

^a ASTRAZENECA R AND D   (Sweden)

^b ASTRAZENECA R AND D   (Sweden)

^c ASTRAZENECA   (United Kingdom)

Author keywords

carcinogenesis; PPAR; tesaglitazar; VEGF

Indexed keywords

FENOFIBRATE; METFORMIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; ROSIGLITAZONE; ROSUVASTATIN; TESAGLITAZAR; VASCULOTROPIN; VASCULOTROPIN RECEPTOR 2;

ANGIOSARCOMA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTOPSY; BLOOD SAMPLING; CARCINOGENICITY; CELL PROLIFERATION; CELL STRESS; CELL VACUOLE; CONCENTRATION RESPONSE; CONTROLLED STUDY; ENDOTHELIUM CELL; EXPERIMENTAL STUDY; FEMALE; HAMSTER; HISTOPATHOLOGY; HUMAN; HUMAN CELL; IMMUNOHISTOCHEMISTRY; IN VITRO STUDY; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LIVER HEMANGIOMA; LIVER HYPERTROPHY; MALE; MAXIMUM PLASMA CONCENTRATION; NONHUMAN; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; PROTEIN EXPRESSION; TOXICITY TESTING; UMBILICAL VEIN ENDOTHELIAL CELL;

ALKANESULFONATES; ANIMALS; AREA UNDER CURVE; CARCINOGENICITY TESTS; CELL PROLIFERATION; CRICETINAE; FEMALE; GENE EXPRESSION PROFILING; HEMANGIOMA; HEMANGIOSARCOMA; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; IMMUNOHISTOCHEMISTRY; LIVER; LIVER NEOPLASMS, EXPERIMENTAL; MALE; PHENYLPROPIONATES; PPAR ALPHA; PPAR GAMMA; STATISTICS, NONPARAMETRIC; VASCULAR ENDOTHELIAL GROWTH FACTOR A;

ANIMALIA; CRICETINAE; RODENTIA;

EID: 84862907690     PISSN: 01926233     EISSN: 15331601     Source Type: Journal    
DOI: 10.1177/0192623311429972     Document Type: Article

References (42)

1. Artwohl M. Fürnsinn C. Waldhäusl W. Hölzenbein T. Rainer G. Freudenthaler A. Roden M. Baumgartner-Parzer S. M. (2005). Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a Pparγ-independent mechanism. Diabetologia 48, 586–94.
2. Baba T. Shimada K. Neugebauer S. Yamada D. Hashimoto S. Watanabe T. (2001). The oral insulin sensitiser, thiazolidinedione, increases plasma vascular endothelial growth factor in type 2 diabetic patients. Diabetes Care 24, 953–54.
3. Barak Y. Liao D. He W. Ong E.S. Nelson M. C. Olefsky J. M. Boland R. Evans R. M. (2002). Effects of peroxisome proliferators-activated receptor δ on placentation, adiposity and colorectal cancer. Proc Natl Acad Sci U S A 99, 303–8.
4. Bustin S. A. (2000). Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J Mol Endocrinol 25, 169–93.
5. Cattley R. C. Deluca J. Elcombe C. Fenner-Crisp P. Lake B. G. Marsman D. S. Pastoor T. A. Popp J. A. Robinson D. E. Schwetz B. Tugwood J. Wahli W. (1998). Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol 27(1 Part 1), 47–60.
6. Cohen A. J. Grasso P. (1981). Review of the hepatic response to hypolipidaemic drugs in rodents and assessment of its toxicological significance to man. Food Cosmet Toxicol 19, 585–605.
7. Cohen S. M. (2005). Effects of Pparγ and combined agonists on the urinary tract of rats and other species. Toxicol Sci 87, 322–27.
8. Cohen S. M. Cook J. C. Doerrer N. G. Hammond T. (2006). Carcinogenic modes of action of PPAR agonists: The HESI Initiative [abstract]. Japanese Society of Toxicology, Nagoya, Japan.
9. Cohen S. M. Storer R. D. Criswell K. A. Doerrer N. G. Dellarco V. L. Pegg D. G. Wojcinski Z. W. Malarkey D. E. Jacobs A. C. Klaunig J. E. Swenberg J. A. Cook J. C. (2009). Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance. Toxicol Sci 111, 4–18.
10. Cronet P. Petersen J. F. Folmer R. Blomberg N. Sjoblom K. Karlsson U. Lindstedt E. L. Bamberg K. (2001). Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure 9, 699–706.
11. Dontenwill W. Chevalier H. J. Harke H. P. Lafrenz U. Reckzen G. (1973). Spontaneous tumors in golden hamsters [Author’s transl]. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 80, 127–58.
12. El Hage J. (2005). Peroxisome proliferation-activated receptor agonists: Carcinogenicity findings and regulatory recommendations. Presented at the International Atherosclerosis Society Symposium on PPAR, Monte Carlo.
13. Emoto M. Anno T. Sato Y. Tanabe K. Okuya S. Tanizawa Y. Matsutani A. Oka Y. (2001). Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes. Diabetes 50, 1166–70.
14. Fagerberg B. Edwards S. Halmos T. Lopantynski J. Schuster H. Stender S. Stoa-Birketvedt G. Tonstad S. Gause-Nilsson I. (2005). Tesaglitazar, a novel dual peroxisome proliferator–activated α/γ agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 48, 1716–25.
15. Feige J. N. Gelman L. Michalik L. Desvergne B. Wahli W. (2006). From molecular action to physiological outputs: Peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog. Lipid Res. 45, 120–59.
16. Goke B. Gause-Nilsson I. Persson A., and the GALLANT 8 Study Group (2007). The effects of tesaglitazar as add-on treatment to metformin in patients with poorly controlled type 2 diabetes. Diabetes Vasc Dis Res 4, 204–13.
17. Hardisty J. F. Elwell M. R. Ernst H. Greaves P. Kolenda-Roberts H. Malarkey D. E. Mann P. C. Tellier P. A. (2007). Histopathology of hemangiosarcomas in mice and hamsters and liposarcomas/fibrosarcomas in rats associated with PPAR agonists. Toxicol Pathol 35, 928–41.
18. Hellmold H. Zhang H. Andersson 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. Evans J. (2007). Tesaglitazar, a PPARalpha/gamma agonist, induces interstitial mesenchymal cell DNA synthesis and fibrosarcomas in subcutaneous tissues in rats. Toxicol Sci 98, 63–74.
19. Herman J. R. Dethloff L. A. McGuire E. J. Parker R. F. Walsh K. M. Gough A. W. Masuda H. de la Iglesia F. A. (2002). Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone. Toxicol Sci 68, 226–36.
20. Hong H. K. Cho Y. M. Park K.-H. Lee C.-T. Lee H. K. Park K. S. (2003). Peroxisome proliferator-activated receptor gamma mediated inhibition of plasminogen activator inhibitor type 1 production and proliferation of human umbilical vein endothelial cells. Diabetes Res Clin Pract 62, 1–8.
21. Kim D. J. Bility M. T. Billin A. N. Willson T. M. Gonzalez F. J. Peters J. M. (2006). Pparβ/δ selectively induces differentiation and inhibits cell proliferation. Cell Death Diff 13, 53–60.
22. Kitajima S. Liu E. Morimoto M. Koike T. Yu Y. Watanabe T. Imagawa S. Fan J. (2005). Transgenic rabbits with increased VEGF expression develop hemangiomas in the liver: A new model for Kasabach-Merritt syndrome. Lab Invest 85, 1517–27.
23. Klaassen C. D. Hood A. M. (2001). The microsomal enzyme inducers on thyroid follicular cell proliferation and thyroid hormone metabolism. Toxicol Pathol 29, 34–40.
24. Klaunig J. D. Babich M. A. Baetcke K. P. Cook J. C. Corton J. C. David R. M. DeLuca J. G. Lai D. Y. McKee R. H. Peters J. M. Fenner-Crisp P.A. (2003). PPARa agonist-induced rodent tumors: Modes of action and human relevance. Crit Rev Toxicol 33, 655–780.
25. Lake B. G. Evans J. G. Cunninghame M. E. Price R. J. (1993). Comparison of the hepatic effects of nafenopin and WY-14,643 on peroxisome proliferation and cell replication in the rat and Syrian hamster. Environ Health Perspect. Dec;101 Suppl 5: 241–7.
26. Lake B. G. (1995). Mechanisms of hepatocarcinogenicity of peroxisome-proliferating drugs and chemicals. Annu Rev Pharmacol Toxicol. 35, 483–507.
27. Lee C.-H. Olson P. Evans R. M. (2003). Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator–activated receptors. Endocrinology 144, 2201–7.
28. Lehrke M. Lazar M. A. (2005). The many faces of Pparγ. Cell 123, 993–99.
29. Ljung B. Bamberg K. Dahllof B. Kjellstedt A. Oakes N.D. Ostling J. Svensson L. Camejo G. (2002). AZ242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. J Lipid Res 43, 855–63.
30. Leppänen P. Kholová I. Mähönen A. J. Airenne K. Koota S. Mansukoski H. Närväinen J. Wirzenius M. Alhonen L. Jänne J. Alitalo K. Ylä-Herttuala S. (2006). Short and long-term effects of hVEGF-A(165) in Cre-activated transgenic mice. PLoS One 1, e13.
31. McClain R. (1989). The significance of hepatic microsomal enzyme induction and altered thyroid function in rats: Implications for thyroid gland neoplasia. Toxicol Pathol 17, 294–306.
32. Meek M. E. Bucher J. R. Cohen S. M. Dellarco V. Hill R. N. Lehman-McKeeman L. D. Longfellow D. G. Pastoor T. Seed J. Patton D. E. (2003). A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol 33, 591–653.
33. Morimura K. Cheung C. Ward J. M. Reddy J. K. Gonzalez F. J. (2006). Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor alpha to Wy-14,643-induced liver tumorigenesis. Carcinogenesis 27, 1074–80.
34. Nambiar P. R. Kirchain S. M. Courmier K. Xu S. Taylor N. S. Theve E. J. Patterson M. M. Fox J. G. (2006). Progressive proliferative and dysplastic typhlocolitis in aging syrian hamsters naturally infected with Helicobacter spp.: A spontaneous model of inflammatory bowel disease. Vet Pathol 43, 2–14.
35. Nesto R. W. Bell D. Bonow R. O. Fonseca V. Grundy S. M. Horton E. S. Winter M. L. Peters J. M. Hennuyer N. Staels B. Fruchart J. C. Fievet C. Gonzalez F. J. Auwerx J. (1997). Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor α-deficient mice. J Biol Chem 272, 27307–12.
36. Pour P. Mohr U. Althoff J. Cardesa N. Kmoch N. (1976). Spontaneous tumors and common diseases in two colonies of Syrian hamster. II. Respiratory tract and digestive system. J Natl Cancer Inst 56, 937–48.
37. Price R. J. Evans J. G. Lake B. G. (1992). Comparison of the effects of nafenopin on hepatic peroxisome proliferation and replicative DNA synthesis in the rat and Syrian hamster. Food Chem Toxicol 30, 937–44.
38. Ratner R. E. Parikh S. Tou C., and the GALLANT 9 Study Group. (2007). Efficacy, safety and tolerability of tesaglitazar when added to the therapeutic regimen of poorly controlled insulin-treated patients with type 2 diabetes. Diabetes Vasc Dis Res 4, 214–21.
39. Rozen S. Skaletsky H. J. (2000) Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S. Misener S. (eds) Bioinformatics Methods and Protocols: Methods in Molecular Biology. Humana Press, Totowa, NJ, pp 365–386. Source code available at http://fokker.wi.mit.edu/primer3/.
40. Schuster H. Fagerberg B. Edwards S. Halmos T. Lopatynski J. Stender S. Birketvedt G. S. Tonstad S. Gause-Nilsson I. Halldorsdottir S. Ohman K. P. (2008). Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance. Atherosclerosis 197, 355–62.
41. Van Hoosier G. L. McPherson C. W., eds. (1987). Laboratory Hamsters. Academic Press, Orlando, FL.
42. Wilding J. P. Gause-Nilsson I. Persson A., and the GALLANT 7 Study Group. (2007). Tesaglitazar, as add-on therapy to sulphonylurea, dose-dependently improves glucose and lipid abnormalities in patients with type 2 diabetes. Diabetes Vasc Dis Res 4, 194–203.