Antiangiogenesis agents avastin and erbitux enhance the efficacy of photodynamic therapy in a murine bladder tumor model

Abstract

Photodynamic therapy (PDT) has been established as an alternative therapy for the treatment of various types of malignant disorders, including oesophageal, lung, and bladder cancer. However, one of the limitations of PDT is treatment-induced hypoxia that triggers angiogenesis. The objective of this study was to evaluate the effects of combination therapy with PDT and an antiangiogenic protocol using monoclonal antibodies against both vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In vitro angiogenesis assays and in vivo matrigel assay were performed to understand the inhibitory effects of the antiangiogenic agents. Tumor bearing mice were assigned to six different categories: Control, PDT only, Avastin + Erbitux, PDT + Avastin, PDT + Erbitux, and PDT + Avastin and Erbitux. Treated and control tumors were monitored for recurrence for up to 90 days. In vitro results provided valuable insight into the dynamics of endothelial cells in response to angiogenic stimulants and inhibitors to assess the angiogenesis processes. Addition of VEGF increased the migration of bladder cancer cells and addition of Avastin and Erbitux decreased cell migration significantly. Both inhibitors were also able to suppress invasion and tube formation in human umbilical vein endothelial cells (HUVEC). The in vivo tumor response for PDT with single inhibitor (Avastin or Erbitux) and double inhibitor (Avastin + Erbitux) was comparable; however, targeting both VEGF and EGFR pathways along with PDT resulted in more rapid response. Downregulation of VEGF and EGFR were observed in tumors treated with PDT in combination with Avastin and Erbitux respectively. Our results show that blocking the VEGF or EGFR pathway along with PDT can effectively suppress tumor growth and the combination of both VEGF and EGFR inhibitors along with PDT could be used to treat more aggressive tumors to achieve rapid response.