Seven novel and potent Raf small molecule kinase inhibitors were evaluated in 7-day oral repeat-dose rat toxicity studies. All compounds tested induced hyperplasia in multiple tissues. Microarrays were used to investigate transciptional changes associated by treatment with a single compound to gain insight into the cellular changes that may contribute to the tissue hyperplasia.
Overall design
Two groups (25 females/group) received oral daily dosing for 7 days of either Vehicle or compound C1 dosed at 100 mg/kg. Five animals from each group were euthanized on Days 1 (4-5 hrs post first dose; received 1 dose), 2 (received 1 dose), 3 (received 2 doses), 5 (received 4 doses) and 8 (received 7 doses). Bladder tissues were collected and profiled at all five time points. Stomach tissues were collected and profiled at the earliest two time points. A single day 3 animal was not available for genomic profiling; therefore, expression data was collected for a total of 49 bladder and 20 stomach samples.
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