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AIMS

ET-A antag. Saline. Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable parameter to improve drug delivery.

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AIMS

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  1. ET-A antag. Saline Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable parameter to improve drug delivery. Philippe Martinive1, Julie DeWever1, Caroline Bouzin1, Pierre Sonveaux1, Christine Baudelet2, Vincent Grégoire3, Bernard Gallez2, Olivier Feron1 UCL Medical School, 1Pharmacology & Therapeutics Unit (FATH 5349), 2Biomedical Resonance Magnetic, 3Center for Molecular Imaging and Experimental Radiotherapy, Ave E. Mounier 53, B-1200 Brussels, Belgium (feron@mint.ucl.ac.be) INTRODUCTION • Tumor Blood flow heterogeneities impairs drug delivery and chemotherapy efficacy. • 2.Pericytes covering endothelial tubes qive them the ability to react to substances present into the tumor. • 3.Endothelin 1 known as a growth factor in oncology but also as a potent vasoconstrictor in cardiology. AIMS 1.To characterize the effects of an ET-1 antagonist on the tumor vascular tone and blood flow heterogeneities. 2. To modulate the ET-1 pathway to improve tumor response to chemotherapy. RESULTS 1. Specific tumor vascular reactivity: Endothelin Receptor A antagonist 2. ET-A antag. decreases blood flow heterogeneities Co-opted tumor arteriole Saline ET-A antag. Hoechst 33342 labeling (blue) and CD31-immunostained tumor vasculature (red) Laser Doppler Needle Isolated tumor and size-matched arterioles (myography) 3. ET-A antag. improves « global» tumor perfusion (DCE-MRI) 4. ET-A antag. «qualitatively» improves tumor perfusion (DCE-MRI) Saline (I.P.) Before ET-A antag. Blood flow [P792] (mM) ET-1 ET-A antag. ET-A antag. (I.P. 1mg/kg) After ET-A antag. Time (min) After [P792] (mM) constriction Before Blood flow Tumor perfused voxels Time (min) Tumor contrast agent concentration 5. ET-A antag. increases IFP 6. ET-A antag. improves the efficacy of conventional chemotherapy Saline ET-A antag. 25-nm fluorescent microspheres (red) and CD-31-immunostained tumor/muscle vasculature (green) Chemotherapy, Cyclophos. I.P. (100mg/kg, d0 and d6; 25mg/kg, d0 and d1) co-injected with ET-A antag. « Wick-in-Needle » CONCLUSIONS • Endogenous ET-1 production largely participates in the tumor blood flow heterogeneities. • ET-A antag. may wipe out such heterogeneities and improves the delivery of chemotherapeutic drugs. This work is supported by grants from the FNRS (FRSM - Télévie), the J. Maisin Fundation, the Belgian Federation against Cancer and the Fortis Cancerology Research Fund.

  2. ET-A antag. Saline ET-A antagonist Treatment: Consequences Implications for drugs delivery Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable parameter to improve drug delivery. Philippe Martinive1, Julie DeWever1, Caroline Bouzin1, Pierre Sonveaux1, Christine Baudelet2, Vincent Grégoire3, Bernard Gallez2, Olivier Feron1 UCL Medical School, 1Pharmacology & Therapeutics Unit (FATH 5349), 2Biomedical Resonance Magnetic, 3Center for Molecular Imaging and Experimental Radiotherapy, Ave E. Mounier 53, B-1200 Brussels, Belgium (feron@mint.ucl.ac.be) INTRODUCTION • Tumor Blood flow heterogeneities impairs drug delivery and chemotherapy efficacy. • 2.Pericytes covering endothelial tubes qive them the ability to react to substances present into the tumor. • 3.Endothelin 1 known as a growth factor in oncology but also as a potent vasoconstrictor in cardiology. AIMS 1.To characterize the effects of an ET-1 antagonist on the tumor vascular tone and blood flow heterogeneities. 2. To modulate the ET-1 pathway to improve tumor response to chemotherapy. RESULTS 1. Specific tumor vascular reactivity: Endothelin Receptor A antagonist 2. ET-A antag. decreases blood flow heterogeneities Co-opted tumor arteriole Saline ET-A antag. Hoechst 33342 labeling (blue) and CD31-immunostained tumor vasculature (red) Laser Doppler Needle Isolated tumor and size-matched arterioles (myography) 3. ET-A antag. improves « global» tumor perfusion (DCE-MRI) 4. ET-A antag. «qualitatively» improves tumor perfusion (DCE-MRI) Saline (I.P.) Before ET-A antag. [P792] (mM) ET-A antag. (I.P. 1mg/kg) After ET-A antag. Time (min) After [P792] (mM) Before Tumor perfused voxels Time (min) Tumor contrast agent concentration 5. ET-A antag. increases IFP 6. ET-A antag. improves the efficacy of conventional chemotherapy Saline ET-A antag. 25-nm fluorescent microspheres (red) and CD-31-immunostained tumor/muscle vasculature (green) Chemotherapy, Cyclophos. I.P. (100mg/kg, d0 and d6; 25mg/kg, d0 and d1) co-injected with ET-A antag. « Wick-in-Needle » CONCLUSIONS • Endogenous ET-1 production largely participates in the tumor blood flow heterogeneities. • ET-A antag. may wipe out such heterogeneities and improves the delivery of chemotherapeutic drugs. This work is supported by grants from the FNRS (FRSM - Télévie), the J. Maisin Fundation, the Belgian Federation against Cancer and the Fortis Cancerology Research Fund.

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