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Urothelial Carcinogenesis in the Urinary Bladder of Rats Treated with Naveglitazar, a -dominant PPAR / Agonist: Lack of Evidence for Urolithiasis as an Inciting Event

¹ Lilly Research Laboratories, Greenfield, Indiana, USA
² Covance Laboratories, Madison, Wisconsin, USA and
³ PAI, Charles River, Frederick, Maryland, USA

Correspondence: Address correspondence to: Gerald G. Long, Eli Lilly and Company, Lilly Research Laboratories, P.O. Box 708, Greenfield, IN 46140; e-mail: Long_ gerald_g{at}lilly.com.

Naveglitazar, a -dominant peroxisome proliferator-activated receptor (PPAR) / dual agonist, was tested for carcinogenicity in F344 rats in a 2-year study. Changes in urine composition and urothelial morphology were characterized in a companion 18-month investigative study. A significant increase in neoplasms of the bladder occurred only in females of the high-dose group (14/60) in the carcinogenicity study. Trends toward increased cell proliferation in the urothelium were noted in both sexes at all time points evaluated in the 18-month study. Group means for urothelial mitogenesis were increased statistically significantly only in high-dose females at 12 and 18 months. Urothelial hyperplasia occurred in high-dose females at 18 months. Morphologic changes in the urothelium at earlier time points were limited to hypertrophy and decreased immunolabeling of the superficial cells for cytokeratin 20 (a marker of terminal differentiation in urothelial cells) in both males and females. No treatment-related changes in urinary parameters, including urinary sediments, were associated with the occurrence of urothelial proliferation. Urinary pH was unaffected by treatment in both males and females, but expected diurnal changes were demonstrated. Collectively, these data indicate that naveglitazar was associated with hypertrophic and proliferative effects on the urothelium, but a link with changes in urinary parameters was not demonstrated.

Key Words: PPAR agonist • carcinogenesis • urothelium • urolithiasis • urinary bladder • rats

Abbreviations: BrdU, bromodeoxyuridine • CK, cytokeratin • EGF, epithelial growth factor • EGFR, epithelial growth factor receptor • H&E, hematoxylin and eosin stain • PPAR, peroxisome proliferator-activated receptor • SEM, scanning electron microscopy • TEM, transmission electron microscopy • TZD, thiazolidinedione • ULLI, unit length labeling index • VEGF, vascular endothelial growth factor

Toxicologic Pathology, Vol. 36, No. 2, 218-231 (2008)
DOI: 10.1177/0192623307311757


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