nsc-600032 and Neoplasm-Metastasis

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.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Hypoxia; Cell Movement; Drug Resistance, Neoplasm; G2 Phase Cell Cycle Checkpoints; Humans; Neoplasm Metastasis; Neovascularization, Pathologic; Spindle Apparatus; Stilbenes; Tubulin Modulators

A rat model was developed to enable direct administration of hyperpolarized. Rat P22 sarcomas were implanted into the right inguinal fat pad of BDIX rats such that the developing tumors received their principle blood supply directly from the right superior epigastric artery. Hyperpolarized. Intra-arterial infusion of hyperpolarized. The model maximizes tumor substrate/drug delivery and minimizes T

Topics: Animals; Arteries; Carbon Isotopes; Drug Delivery Systems; Epigastric Arteries; Female; Femoral Vein; Gadolinium; Magnetic Resonance Spectroscopy; Male; Neoplasm Metastasis; Neoplasms; Optical Imaging; Perfusion; Phosphorylation; Pyruvic Acid; Rats; Spectrophotometry; Stilbenes