Abstract
1295
Approximately 70% of muscle-invasive bladder cancers express the epidermal growth factor receptor (EGFR) and expression is associated with poor prognosis. Recent evidence suggests that irradiation can stimulate EGFR resulting in activation of intracellular cytoprotective signaling cascades. Thus, inhibition of EGFR function, e.g. using a small molecule tyrosine kinase inhibitor (TKI), may be a means of enhancing the radio-responsiveness of bladder tumors. Six bladder cancer cell lines with variable EGFR expression levels were treated with the EGFR-TKI, gefitinib (‘Iressa’, ZD1839), ionizing radiation (IR) or combined gefitinib/IR. Growth inhibition rates were assessed using both MTT and clonogenic assays. Growth inhibition rates determined with IR alone and combined gefitinib/IR were compared to calculate the dose enhancement ratio (DER) achieved with the use of gefitinib in each cell line. Subsequently, EGFR expression levels in each cell line were determined using Western blotting and related to the previously calculated DER. Treatment with gefitinib and IR alone resulted in dose-dependent growth inhibition in all six cell lines (IC50 gefitinib 0.18-2.48 μM). In all six cell lines assessed using clonogenic assay the combination of gefitinib and IR resulted in significantly greater growth inhibition than treatment with either gefitinib or IR alone (Student’s t-test, p=0.001-0.04; DER 1.19-2.00). The enhancement of growth inhibition achieved using combined gefitinib and IR was significant in five of the six cell lines assessed by MTT assay (Student’s t-test, p=0.001-0.03; DER 1.38-2.08). There was no correlation between EGFR expression levels and DERs (Pearson’s correlation; clonogenic assay, r=0.318, p=0.539; MTT assay, r=0.206, p=0.695). Radiosensitization can be achieved in bladder cancer cell lines by the addition of gefitinib to IR. Repetition of these in vitro findings using an in vivo model (work currently underway) would provide sound justification for translating this work into a clinical trial. ‘Iressa’ is a trademark of the AstraZeneca group of companies.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]