Enhanced response to C225 of A431 tumor xenografts growing in irradiated tumor bed

Abstract

BACKGROUND AND PURPOSE: We recently demonstrated that C225 maintenance therapy after completion of radiotherapy further increased tumor radiocurability. The present study assessed mechanisms underlying the observed improvement in C225 efficacy in pre-irradiated tissue (tumor bed). MATERIALS AND METHODS: A431 xenografts growing in pre-irradiated and non-irradiated tissue were treated with C225. Tumors were assessed for growth delay, cell proliferation, hypoxia, EGFR and VEGF expressions. In vitro clonogenic survival of cells derived from these tumors was also assayed. RESULTS: Pre-irradiation of tumor bed induced growth retardation, reduction in Ki-67 labeling, and overexpression of HIF-1alpha, CA IX, EGFR and VEGF biomarkers. C225 treatment dramatically inhibited tumor growth in the irradiated tumor bed (P<0.0001), which was associated with further reduction in Ki-67 labeling, and reduced expression of HIF-1alpha, CA IX, EGFR and VEGF. Cells derived from tumors in the pre-irradiated bed showed increased sensitivity to C225. C225 was more cytotoxic against hypoxic than well-oxygenated A431 cells grown in vitro. CONCLUSION: A431 xenografts growing in pre-irradiated tumor bed exhibit enhanced sensitivity to C225. Pre-irradiated tissue microenvironment seems to render tumor cells more susceptible to C225 cytostatic and cytotoxic actions. If confirmed in other tumor models these findings support the use of C225 maintenance therapy after completion of radiotherapy.