Identification and Development of Vascular Disrupting Agents: Natural Products That Interfere with Tumor Growth

Abstract

Despite rapid progress made in understanding the biological mechanism regulating developmental and tumor vasculature, the clinical success of targeted therapeutics that interfere with key molecular and cellular pathways of angiogenesis has been limited by a lack of improved patient survival when these agents were administered as single agents. These findings indicate a redundancy of mechanisms regulating blood vessel formation, leading to tumor refractoriness to anti-­angiogenic treatment. In contrast, vascular disruptive agents (VDAs) induced rapid regression of established tumors in preclinical studies. For several classes of VDAs, including the natural products flavonoids, colchicines and vincas, it was demonstrated that the effects on the vascular compartment diverge from that on the tumor parenchyma and are both anti-angiogenic (vascular stasis/prevention) and vascular disrupting (vascular regression)—resulting in catastrophic insults to the nascent vasculature. Vascular endothelial cells (ECs) are exquisitely dependent on the tubulin cytoskeleton for essential functions, including invasion, proliferation, migration, tube formation, and cell signaling—hallmarks of tumor angiogenesis. However, the clinical development of VDAs was frequently hampered by their narrow therapeutic index, limiting the use of these compounds due to side effects in the normal vasculature and/or other normal tissues. In this chapter we review the progress made to identify VDAs in oncology, with focus on preclinical and clinical studies. The identification of novel natural products and therapeutic compounds with improved potency and safety characteristics continue to keep great promise to overcome the limitations of first generation VDAs.