Tumor promoting effects of the PPAR gamma agonist rosiglitazone during the progression stages of OH-BBN induced urinary bladder cancer

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 1663 While examining the PPAR agonist rosiglitazone as a potential chemopreventive agent, a large increase in hydroxybutyl(butyl)nitrosamine (OH-BBN) induced urinary bladder cancers was observed. In the initial study, Fisher-344 female rats were administered OH-BBN (2x/week), 150 mg/gavage, for eight weeks. One week following the last dose of OH-BBN, rats were administered rosiglitazone by gavage for the remainder of the study (6 months). Twenty-seven percent of OH-BBN treated animals developed large urinary bladder cancers during the course of the study, while 72% of carcinogen treated rats that also received rosiglitazone (50 mg/kg BW/day) developed large palpable tumors (P<0.01). When measured at the end of the study (9 months after the initial OH-BBN treatment) roughly 50% of controls vs 100% of rosiglitazone treated rats developed large tumors. Surprisingly, examination of PPAR gamma by immunohistochemistry in the urinary bladders of rats showed that while untreated bladder epithelium and bladder hyperplasias highly expressed PPAR, established cancers exhibited strikingly lower levels. PPAR levels in tumors were not increased by treatment with rosiglitazone. In a second study, lower doses of rosiglitazone (10, 2 and 0.4 mg/kg BW/day) were evaluated. The higher dose strongly promoted cancer formation (P<0.01). The middle dose, which is slightly lower than a standard human dose, significantly increased bladder tumor formation (P<0.05). The lowest dose did not significantly increase tumor formation, although the incidence of large tumors in treated rats was greater than control rats (66% vs 42%). Rosiglitazone alone (10 mg/kg BW/day) given in the absence of OH-BBN did not result in bladder tumor formation when given for 9 months. In a separate experiment employing the RXR agonist Targretin (which may have many similar effects to a pure PPAR gamma agonist), an increase in urinary bladder cancers and weight of the cancers was similarly observed.