TY - JOUR T1 - Combretastatins: More Than Just Vascular Targeting Agents? JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 212 LP - 227 DO - 10.1124/jpet.115.226225 VL - 355 IS - 2 AU - Lisa M. Greene AU - Mary J. Meegan AU - Daniela M. Zisterer Y1 - 2015/11/01 UR - http://jpet.aspetjournals.org/content/355/2/212.abstract N2 - Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives. Furthermore, tubulin is a highly validated molecular target of many direct anticancer agents routinely used as front-line chemotherapeutics. The unique vascular targeting properties of the combretastatins have somewhat overshadowed their development as direct anticancer agents and the delineation of the various cell death pathways and anticancer properties associated with such chemotherapeutics. Moreover, the ongoing clinical trial of OXi4503 (combretastatin-A1 diphosphate) together with preliminary preclinical evaluation for the treatment of refractory acute myelogenous leukemia has successfully highlighted both the indirect and direct anticancer properties of combretastatins. In this review, we discuss the development of the combretastatins from nature to the clinic. The various mechanisms underlying combretastatin-induced cell cycle arrest, mitotic catastrophe, cell death, and survival are also reviewed in an attempt to further enhance the clinical prospects of this unique class of VTAs. ER -