Targeting the Vasculature of Colorectal Carcinoma with a Fused Protein of (RGD) ₃‐tTF

Abstract

Purpose. Truncated tissue factor (tTF) fusion protein targeting tumor vasculature can induce tumor vascular thrombosis and necrosis. Here, we generated (RGD)3-tTF in which three arginine-glycine-aspartic (RGD) targeting integrin α v β 3 and tTF induce blood coagulation in tumor vessels. Methods. The bioactivities of (RGD)3-tTF including coagulation activity, FX activation, and binding with integrin α v β 3 were performed. The fluorescent labeled (RGD)3-tTF was intravenously injected into tumor-bearing mice and traced in vivo. The tumor growth, volume, blood vessel thrombosis, tumor necrosis, and survival time of mice treated with (RGD)3-tTF were evaluated. Results. The clotting time and FX activation of (RGD)3-tTF were similar to that of TF (P > 0.05) but different with that of RGD (P < 0.05). (RGD)3-tTF presented a higher binding with α v β 3 than that of RGD and TF at the concentration of 0.2 μmol/L (P < 0.05). (RGD)3-tTF could specifically assemble in tumor and be effective in reducing tumor growth by selectively inducing tumor blood vessels thrombosis and tumor necrosis which were absent in mice treated with RGD or TF. The survival time of mice treated with (RGD)3-tTF was higher than that of mice treated with TF or RGD (P < 0.05). Conclusion. (RGD)3-tTF may be a promising strategy for the treatment of colorectal cancer.

Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties

“…The introduction of the glycine moiety showed a remarkable performance of the valproylglycine hydrazide-hydrazone derivatives compounds 12a-e. The inhibitions of developmental angiognesis by valproylglycine hydrazide is not surprising, as quite recently, the tumor growth reduction by selectively inducing tumor blood vessels thrombosis and tumor necrosis in tumor bearing mouse has been reported by synthetic polypeptides having glycine as one of the residue (Liu et al, 2011b;Huang et al, 2013;Zhao et al, 2013). Besides interfering with angiogenic blood vessels formation, the compounds from valproylglycine hydrazide series also induced severe cardiac edema (Figure 1 black arrow in D).…”

RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice

“…It is demonstrated that equimolar concentration of coagulase suffices for activation of prothrombin. Conversely, TF fusion proteins require high concentration, for instance (RGD) 3 -tTF generated by Huanget et al ., activated FX at 1 μ mol/L or higher concentration 25 . Nevertheless, tCoa fusion proteins required nanomolar concentrations of coagulase to initiate coagulation by activation of prothrombin 21 .…”

NGR (Asn-Gly-Arg)-targeted delivery of coagulase to tumor vasculature arrests cancer cell growth

“…It is reported that coagulase at concentrations as low as 1 × 10 −16 M is sufficient for thrombin activation in vitro [ 37 ]. Compared to coagulase, tissue factor fusion proteins demand higher concentrations, equal to or more than 1 µmol/L [ 38 ]. In our study, nanomolar concentrations sufficed to initiate coagulation of blood.…”