The effects of the EGFr inhibitor
Iressa on development of urinary bladder
cancers induced by hydroxybutyl(butyl)
nitrosamine (
OH-BBN) in rats were examined.
Iressa treatment (4.5 or 1.5 mg/kg BW/day) beginning one week after the last dose of
OH-BBN decreased the occurrence of large (>200 mg)
bladder cancers at termination of the study by 75 and 52%, respectively. Treatment with
Iressa (10 mg/kg BW/day) beginning one week or three months (delayed initiation) after the last dose of
OH-BBN also significantly increased
tumor latency and decreased the incidence of palpable
bladder cancers. In the delayed initiation study, microscopic
cancers already existed when treatment was initiated; implying that the effects of
Iressa occur late in
tumor progression. Potential pharmacodynamics and/or efficacy
biomarkers modulated by short-term exposure (5 day) to
Iressa (10 mg/kg BW/day) were determined in palpable bladder lesions by using three different approaches: i) direct immunohistochemical examination of EGFr related
proteins; which showed that phosphorylated EGFr, AKT and ERK were significantly decreased; ii) measurement of
protein expression by two dimensional gel electrophoresis and tandem mass spectrometry. This showed that the
Annexin A2,
MAP kinase kinase and
nucleolin (all
proteins associated with the
VEGF pathway) were decreased in treated
tumors; and iii) measurement of gene expression determined in gene microarrays demonstrated that numerous pathways were markedly altered by
Iressa treatment. In particular, cell cycle genes related to the anaphase
protein complex (APC) pathway, including CDC 20, cyclin B1, BUB1 and both of the
Aurora kinases, were significantly decreased.