Abstract
Abstract The preventive effects of the EGFr inhibitor Iressa on the induction of urinary bladder cancers induced by OH-BBN was determined. Treatment of rats with Iressa (10 mg/kg BW/day) beginning two weeks after the last dose of OH-BBN decreased the incidence of large palpable bladder cancer lesions by 95% at an 8-month observation period. Treatment with lower doses of Iressa (4 and 1.33 mg/kg BW/day) decreased the incidence of large tumors by 80 and 65%, respectively. This preventive efficacy was similarly observed when one examined an incidence curve; i.e., a large increase in tumor latency. At 3 1/2 months after the last OH-BBN dose, 75% of the rats had already developed microscopic cancers. Iressa treatment beginning at this time period also lowered the incidence of large tumors; implying that most of the effects of Iressa were during the latter periods of tumor progression. We also examined potential biomarkers modulated by short-term exposure to Iressa (10 mg/kg BW/day) in urinary bladder cancers. Three approaches were taken to identify biomarkers: (1) Alterations in EGFr related proteins directly associated with the efficacy of Iressa by immunohistochemistry. Levels of various biomarkers (phosphorylated EGFr, phosphorylated AKT, but not phosphorylated ERK levels were significantly decreased in the bladder tumors of treated rats. (2) Alterations in protein expression when comparing control and Iressa treated tumors. Employing two-dimensional gel electrophoresis and tandem mass spectrometry, it was found that proteins associated with the angiogenic effects of VEGF were decreased in tumors from treated animals. These included cytoskletal proteins nucleolin, annexin A1 and the MAP kinase (MAPKK). (3) Alterations in gene expression employing array gene technology. Numerous metabolic and cellular pathways were markedly altered by Iressa treatment, most particularly cell cycle related genes; i.e., there were strong inhibition of expression of CDC20 and both of the aurora kinases. Thus, we have identified biomarkers that might be relevant as pharmacodynamic or efficacy biomarkers in clinical prevention trials of urinary bladder cancer. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A106.
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