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      Vascular Permeability and Drug Delivery in Cancers

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          Abstract

          The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation. This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia, and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor. Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.

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          Drug resistance and the solid tumor microenvironment.

          Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.
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            A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.

            Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab, a neutralizing antibody against vascular endothelial growth factor, in patients with metastatic renal-cell carcinoma. A randomized, double-blind, phase 2 trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks; the time to progression of disease and the response rate were primary end points. Crossover from placebo to antibody treatment was allowed, and survival was a secondary end point. Minimal toxic effects were seen, with hypertension and asymptomatic proteinuria predominating. The trial was stopped after the interim analysis met the criteria for early stopping. With 116 patients randomly assigned to treatment groups (40 to placebo, 37 to low-dose antibody, and 39 to high-dose antibody), there was a significant prolongation of the time to progression of disease in the high-dose--antibody group as compared with the placebo group (hazard ratio, 2.55; P 0.20 for all comparisons). Bevacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer. Copyright 2003 Massachusetts Medical Society
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              Radical causes of cancer.

              Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals--such as antioxidant scavengers and enzymes--and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.
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                Author and article information

                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                23 June 2013
                15 August 2013
                2013
                : 3
                : 211
                Affiliations
                [1] 1CNRS, UMR8104 , Paris, France
                [2] 2INSERM, U1016 , Paris, France
                [3] 3Sorbonne Paris Cite, Universite Paris Descartes , Paris, France
                Author notes

                Edited by: Fabrizio Marcucci, Istituto Superiore di Sanità, Italy

                Reviewed by: Ronald Berenson, Compliment Corporation, USA; Raffaella Giavazzi, Istituto di Ricerche Farmacologiche “Mario Negri” – IRCCS, Italy

                *Correspondence: Julie Gavard, Institut Cochin, 22 rue Mechain, Room 306, Paris 75014, France e-mail: julie.gavard@ 123456inserm.fr

                Sandy Azzi and Jagoda K. Hebda have contributed equally to this work.

                This article was submitted to Frontiers in Pharmacology of Anti-Cancer Drugs, a specialty of Frontiers in Oncology.

                Article
                10.3389/fonc.2013.00211
                3744053
                23967403
                5b16168f-a3bb-4872-a8ff-fd03869eb86a
                Copyright © 2013 Azzi, Hebda and Gavard.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 May 2013
                : 01 August 2013
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 148, Pages: 14, Words: 10812
                Categories
                Oncology
                Review Article

                Oncology & Radiotherapy
                vegf,permeability,ve-cadherin,endothelial barrier,tumor angiogenesis
                Oncology & Radiotherapy
                vegf, permeability, ve-cadherin, endothelial barrier, tumor angiogenesis

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