Combretastatins: more than just vascular targeting agents?
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.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (L.M.G., D.M.Z.), and School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology (M.J.M.), Trinity College Dublin, Dublin, Ireland greeneli@tcd.ie.
Lisa M
LM
Greene
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (L.M.G., D.M.Z.), and School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology (M.J.M.), Trinity College Dublin, Dublin, Ireland.
Mary J
MJ
Meegan
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute (L.M.G., D.M.Z.), and School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology (M.J.M.), Trinity College Dublin, Dublin, Ireland.
Daniela M
DM
Zisterer
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D008941:Spindle Apparatus / Q000187:drug effects; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013267:Stilbenes; D050257:Tubulin Modulators; C063690:combretastatin A-1; C058728:fosbretabulin