Urothelial carcinogenesis in the urinary bladder of rats treated with naveglitazar, a gamma-dominant PPAR alpha/gamma agonist: lack of evidence for urolithiasis as an inciting event.
Naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma 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.
Long
Gerald G
GG
Lilly Research Laboratories, Greenfield, Indiana 46140, USA. Long_ gerald_g@lilly.com
Reynolds
Vincent L
VL
Lopez-Martinez
Alric
A
Ryan
Thomas E
TE
White
Sandy L
SL
Eldridge
Sandra R
SR
D000818:Animals; D002118:Calcium / Q000652:urine; D015197:Carcinogenicity Tests; D049109:Cell Proliferation / Q000187:drug effects; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D016482:Urinalysis; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000473:pathology; D052878:Urolithiasis / Q000139:chemically induced* / Q000473:pathology; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure
D047495:PPAR gamma; D010666:Phenylpropionates; D002118:Calcium; C517861:naveglitazar