Development of novel antiangiogenic compounds for colorectal cancer using a tumor explant model and zebrafish.

Abstract

e14101 Background: The treatment of metastatic colorectal cancer has significantly improved with the development of novel molecularly targeted drugs such as bevacizumab (Avastin); however response rates are modest (40%). There is an urgent need for the development of newer drugs which target angiogenesis and inflammation more effectively. Historically, initial drug screening has been performed using monolayer cell cultures, but these do not effectively present the entire tumour microenvironment. Novel models are required to investigate newer target lead drugs. Methods: Chemical screens of randomized drug libraries were performed in zebrafish to identify drugs that inhibit developmental angiogenesis. Two lead drugs were then tested using human ex vivo colorectal explants to examine their potential to inhibit angiogenic and inflammatory protein secretions for the following factors VEGF, MCP-1, GRO-alpha, IL-6, TNF, IL-8 and IL-1β. Human explants from 5 patients were cultured for 72 hours, and levels of the above factors were assessed using ELISA. Results: Compound 11B and 11F significantly inhibit intersegmental vessel development in zebrafish. Compound 11B (1 μM) reduced the expression of IL-6 (p=0.02) and the 10 µM concentration reduced the expression of VEGF (p=0.047), IL-6 (p=0.02) and IL-1β (p=0.01). Compound 11F (1 μM) reduced the expression of VEGF (P=0.025) and the 10 µM concentration reduced the expression of VEGF (p=0.01) and IL-1β (p=0.01). Bevacizumab (1 μM) reduced the expression of VEGF (p=0.01) and IL-6 (p=0.02) and the 10 µM concentration reduced the expression of VEGF (p=0.003) and IL-6 (p=0.02). Bevacizumab or the other drugs did not affect the expression of MCP-1, GRO-alpha, TNF and IL-8. Conclusions: These studies have characterised two novel compounds with the potential to become important anti-angiogenic drugs in colorectal cancer.