We evaluated
RS5444, a
thiazolidinedione high affinity
PPARgamma agonist, for the ability to inhibit colon
carcinogenesis in
azoxymethane (AOM)-treated mice. In our initial experiment, mice were treated with
RS5444 during AOM treatment, and the
drug was withdrawn 12 weeks after the last injection of AOM.
RS5444 significantly inhibited aberrant crypt focus formation under these circumstances. Furthermore, exposure to
RS5444 during the course of AOM treatment effectively blocked colon
tumor formation after withdrawal of the agonist.
PPARgamma expression and nuclear localization were reduced in
adenomas.
RS5444 did not inhibit
DNA synthesis in
tumor cells, suggesting that
PPARgamma activity was impaired in
adenomas. To test this hypothesis, pre-existing
adenomas were treated with
RS5444 for 16 weeks. We observed a slight, albeit not statistically significant, reduction in
tumor incidence in RS5444-treated mice. However, histological examination revealed that
tumors from RS5444-treated mice were of significantly lower grade, as evaluated by the extent of dysplasia. Furthermore,
carcinoma in situ was observed in about one-third of control
tumors, but was never observed in RS5444-treated
tumors. We conclude that
RS5444 inhibits both initiation and progression of colon
tumors in the AOM model of sporadic colon
carcinogenesis.