Modulation of tumor angiogenesis through the use of antisense oligodeoxynucleotides targeted to VEGF andbFGF

Angiogenesis is critical for the growth and metastatic spread of solid tumors. It is tightly controlled by specific regulatory factors. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF) have been implicated as the key factors in tumor angiogenesis. The present studies were undertaken to evaluate the effects of blocking VEGF/bFGF production by antisense phosphorothioate oligodeoxynucleotides (AS-ODNs) on the angiogenic activity and growth of a preclinical model of renal cell carcinoma (Caki-1).; Efficient deliveries of AS-ODNs were achieved using cationic liposome (DOTAP:DOPE) based delivery systems both in vitro and in vivo.; AS-ODNs sequences against VEGF and bFGF have been designed and their efficacies were tested in vitro. Effective AS-ODNs against VEGF (V515) and bFGF (B460) were identified. Treatment of Caki-1 cells with V515 or B460 led to a reduction in VEGF or BFGF expression levels sufficient to impair the proliferation and migration potential of co-cultured endothelial cells. The observed effects were AS-ODNs sequence specific, dose dependent and were achieved at a low, non-toxic dose. The treatment of Caki-1 cells with V515 or B460 was also sufficient to impair the Caki-1 tumor cell induced angiogenesis in vivo. When V515 or B460 treated Caki-1 cells were injected into nude mice and evaluated for their angiogenic potential, the number of vessels initiated were significantly reduced.; To test antitumor efficacy of VEGF/bFGF AS-ODNs treatment, V515 and B460 were administrated to Caki-1 xenograft tumor bearing mice. The results showed that systemic administration of VEGF/bFGF AS-ODNs significantly inhibited the growth of Caki-1 tumors. More importantly, a better response was observed when these two AS-ODNs treatments were combined. A combination of VEGF/bFGF AS-ODNs treatment with VEGF/bFGF receptor inhibitor or single dose local radiation also showed enhanced tumor responses when compared to single treatment alone.; These results indicate that AS-ODNs against pro-angiogenic factors VEGF and bFGF may have great utilities in the treatment of renal cell carcinoma either alone or in combination with other anti-cancer therapies.