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Combinatorial Administration of Molecules That Simultaneously Inhibit Angiogenesis and Invasion Leads to Increased Therapeutic Efficacy in Mouse Models of Malignant Glioma

¹ Neurosurgery, Department of Neurological Sciences, University of Milano, Ospedale Maggiore di Milano, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; ² Department of Pharmacology, University of Milano, Milan, Italy; ³ INSERM Unit EMI 0113, Molecular Angiogenesis Laboratory, University of Bordeaux I, Talence, France; and ⁴ Groupe de Chimie Bio-Organique (Institut National de la Santé et de la Recherche Médicale U 577), Université Victor Segalen Bordeaux 2, Bordeaux Cedex, France

Purpose: We investigated the ability of the combinatorial administration of different inhibitors with activities on glioma angiogenesis, migration, and proliferation to produce a prolonged inhibition of glioma growth.

Experimental Design: We combined inhibitors affecting solely tumor angiogenesis (PF-4/CTF, cyclo-VEGI) or inhibitors affecting both angiogenesis and invasion together (PEX, PF-4/DLR).

Results: When administered in combination, these drugs produced a prolonged and increased inhibition of glioma growth independently from the type of inhibitor used. The combinatory administration was more effective than the administration of a single inhibitor alone, and a strong therapeutic response was reached with a significantly lower amount of protein. The strongest inhibition was observed when human PEX and PF-4/DLR, which affect both glioma angiogenesis and invasion by separate mechanisms, were combined.

Conclusions: This supports the concept that prolonged glioma growth inhibition can be achieved by simultaneous delivery of molecules that target both tumor and endothelial cells and acting by separate mechanisms.

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