Targeting the epidermal growth factor receptor in conjunction with Oxaliplatin

5210 The epidermal growth factor receptor (EGFR) is overexpressed in a wide range of solid tumours including colorectal cancer. Targeting of this growth receptor has become an important therapeutic strategy. In this study we assessed the cytotoxic effect of the EGFR tyrosine kinase inhibitor, ZD-1839, in combination with Oxaliplatin in the HCT116 p53 wild type (+/+) and null (-/-) colorectal cancer lines. In addition, we assessed a possible sequence-dependent effect of either drug. Cell viability was assessed using MTT and clonogenic survival assays and analysed by ANOVA. A significant antagonism was observed between ZD-1839 and Oxaliplatin-induced cell death in both cell lines. This effect was most prominent following concomitant treatment and pre-treatment with ZD-1839 for 24 and 48 hours. ZD-1839 treatment resulted in a marked decrease in the sub-G0 cell population as demonstrated by flow cytomety. In addition, ZD-1839 treatment resulted in the dose-dependent inhibition of Oxaliplatin-induced PARP-cleavage. To elucidate the associated cellular mechanism, EGFR phosphorylation was determined following Oxaliplatin treatment. In both cell lines, a dose-dependent decrease in EGFR phosphorylation was observed. In conclusion, we have shown antagonism between Iressa and Oxaliplatin in colorectal cancer cells. This effect appears to be the result of decreased EGFR phosphorylation by Oxaliplatin treatment.