In an initial study to determine if
rosiglitazone had chemopreventive activity, Fischer-344 female rats were administered twice weekly doses of hydroxybutyl(butyl)
nitrosamine (
OH-BBN), a urinary bladder specific
carcinogen, for 8 weeks. Two weeks following the last dose of
OH-BBN, rats were administered
rosiglitazone (50 mg/kg BW) daily by gavage for the remainder of the study (7 months). Only 57% of
OH-BBN-treated animals developed palpable urinary bladder
cancers during the course of the study, while all of the
OH-BBN plus
rosiglitazone treated rats developed large
cancers (p < 0.01). Surprisingly, examination for
PPAR gamma by immunohistochemistry in the urinary bladders of rats showed that while untreated bladder urothelium and preneoplastic lesions clearly expressed
PPAR gamma, frank
carcinomas exhibited significantly lower levels. This was confirmed by employing microarray studies of the same samples. In additional studies, lower doses of
rosiglitazone (10, 2 and 0.4 mg/kg BW/day) were administered. The 10 mg/kg BW/day dose greatly enhanced
bladder cancer incidence (p < 0.01). The dose of 2 mg/kg BW/day, which is roughly equivalent to a standard human dose, also significantly increased
bladder cancer incidence (controls, 48%;
rosiglitazone-treated, 84%). The lowest dose did not significantly increase
tumor incidence (
rosiglitazone at 0.4 mg/kg BW/day, 64%) or
tumor weight in the rats, although there was a trend in that direction.
Rosiglitazone alone (10 mg/kg BW/day) given in the absence of
OH-BBN did not result in
bladder cancer formation when given for 10 months. In summary,
rosiglitazone over a wide dose range enhanced urinary bladder
carcinogenesis in the
OH-BBN model in rats.