Wenyin Shi1, Dietmar W Siemann. 1. Department of Radiation Oncology, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA. wshi@ufl.edu
Abstract
BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis. MATERIALS AND METHODS: Antisense phosphorothiolate oligodeoxynucleotides (PS-ODNs) were used to reduce VEGF production while the small molecule PD0203359-0002 (PD203359) was used to inhibit VEGF/bFGF receptor tyrosine kinase activity. RESULTS: PD203359 exposure was found to profoundly impair the growth of human endothelial cells (HMVEC-L) at doses 20-fold less than those affecting human renal cell carcinoma (Caki-1) cell growth. In vivo, treatment with PD203359 inhibited tumor cell-induced angiogenesis and resulted in a significant tumor growth delay. Treatment with VEGF antisense PS-ODNs also significantly increased the time for tumors to grow to five times the starting size. Most importantly, when the PD203359 and VEGF antisense treatments were combined, a greater antitumor response than could be achieved with either therapy alone was observed. CONCLUSION: Simultaneously targeting VEGF production and VEGF receptor signaling enhances the anticancer efficacy of either therapy alone.
BACKGROUND:Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis. MATERIALS AND METHODS: Antisense phosphorothiolate oligodeoxynucleotides (PS-ODNs) were used to reduce VEGF production while the small molecule PD0203359-0002 (PD203359) was used to inhibit VEGF/bFGF receptor tyrosine kinase activity. RESULTS:PD203359 exposure was found to profoundly impair the growth of human endothelial cells (HMVEC-L) at doses 20-fold less than those affecting humanrenal cell carcinoma (Caki-1) cell growth. In vivo, treatment with PD203359 inhibited tumor cell-induced angiogenesis and resulted in a significant tumor growth delay. Treatment with VEGF antisense PS-ODNs also significantly increased the time for tumors to grow to five times the starting size. Most importantly, when the PD203359 and VEGF antisense treatments were combined, a greater antitumor response than could be achieved with either therapy alone was observed. CONCLUSION: Simultaneously targeting VEGF production and VEGF receptor signaling enhances the anticancer efficacy of either therapy alone.