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In the attempt to limit tumor growth and cancer cell spreading in the organism, and so the formation of metastasis, one of the actual targets in cancer research is stopping angiogenesis. Moreover, selectivity for hypoxia could target solid tumors whilst avoiding side effects on healthy tissues that are normoxic. At the UCL Pharmacognosy group research, a bioguided fractionation has been performed on Cissampelos owariensis, a Beninese plant, in order to identify anti-angiogenesic compounds with selectivity for hypoxia. We identified pheophorbide a, a chlorophyll derivative, as the main compound in the most interesting extract, and also showed that this molecule had no selectivity ty for hypoxia but actually for light, pheophorbide a being photosensitizer. In collaboration with the University of Abomey-Calavi (UAC) in Benin, we also quantified pheo phorbide a concentration in different samples, and demonstrated that environmental factors such as growth place of C. owariensis, climate or ground composition, influence the concentration of pheophorbide a in the plant, rather than the type ("wild" or "cultivated"). Finally, ta prove the importance of the conservation method of vegetal samples after plant harvesting, we demonstrated that dipping fresh plants in boiling water can avoid the formation of chlorophyll derivatives during drying and extraction, which allows the measurement of the initial pheophorbide a content in the plant. Afin de limiter la croissance tumorale ainsi que la propagation de cellules cancéreuses dans l'organisme et donc la formation de métastases, une des cibles actuelles dans la recherche contre le cancer est de bloquer l'angiogenèse. De plus, la sélectivité pour l'hypoxie permettrait de cibler les tumeurs solides en évitant des effets secondaires sur les tissus sains qui sont normoxiques. Au laboratoire de pharmacognosie de l'UCL, un fractionnement bioguidé a été effectué sur Cissampelos owariensis, une plante originaire du Bénin, afin d'identifier des composés anti-angiogéniques posséda nt une activité sélective pour l'hypoxie. Ce fractionnement a permis d'identifier le phéophorbide a, un produit de dégradation chlorophyllien, comme étant le composé majoritaire de l'extrait le plus intéressant. Cependant, la sélectivité à l'hypoxie premièrement mise en évidence s'est avérée être une sélectivité à la lumière, le phéophorbide a étant un composé photoactivable et les tests effectués en hypoxie étant effectués à la lumière tandis que ceux en normoxie étaient réalisés à l'obscurité. Nous avons également, en collaboration avec l'Université d'Abomey-Calavi (UAC) au Bénin, dosé le phéophorbide a dans différents échantillons, ce qui a permis de montrer que des facteurs environnementaux tels que le lieu de culture de Cissampelos owariensis, le climat ou la composition du sol, auraient une plus grande influence sur la concentration en phéophorbide a dans la plante, plutôt que le caractère « sauvage » ou « cultivé » de celle-ci. Finalement, afin de montrer l'importance de la méthode de conservation des échantillons végétaux après récolte, il a été démontré qu'un pré-traitement par ébouillantage empêche la formation de dérivés chlorophylliens lors du séchage et de l'extraction, permettant ainsi de doser la teneur initiale en phéophorbide a dans la plante.

Cissampelos --- Angiogenesis Modulating Agents --- Cell Hypoxia --- Neoplasms

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Cancer is a pathological process caused by the appearance of an abnormal cell which increases in an uncontrolled way. To be able to multiply, the tumoral cells need much oxygen and energy. The more the cell divides, the more it moves away from the vessel which irrigated it. Consequently, the hypoxic areas will be born. To be able to continue to multiply, the cancer cell will have to create new blood-vessels. This phenomenon is called the angiogenesis and started by a growth factor: the VEGF. But these new vessels are dilated, very permeable and will cause plasmatic protein escapes which will increase the pore water pressure. This rise of pressure of tissues towards blood will constitute one of the main barriers of the access of the drugs to the tumor. This is why, improving oxygenation and the tumoral perfusion, via amongst other things the modulation of tonicity and the vascular endothelia, the interstitial pressure decrease or hyperthermia, seems to be a promising track to improve the access of the drug to the tumor.
Some techniques already used in private clinic like the functional imagery or the angiography via CT-scan with iodine already make it possible to characterize these hemodynamics factors. But within sight of the positive results of the various non-invasive tools developed in this memory, a future application in private clinic seems to be possible Le cancer est un processus pathologique provoqué par l’apparition d’une cellule anormale qui se multiplie de façon incontrôlée. Pour pouvoir se multiplier, les cellules tumorales ont besoin de beaucoup d’oxygène et d’énergie. Au plus la cellule se divise, au plus elle s’éloigne du vaisseau qui l’irriguait. Dès lors, naîtront des régions hypoxiques. Pour pouvoir continuer à se multiplier, la cellule cancéreuse va devoir créer de nouveaux vaisseaux sanguins. Ce phénomène est appelé l’angiogenèse et est déclenché par un facteur de croissance : le VEGF. Mais ces nouveaux vaisseaux sont dilatés, très perméables et vont provoquer des fuites de protéines plasmatiques qui augmenteront la pression interstitielle. Cette hausse de pression des tissus vers le sang constituera l’une des barrières principales de l’accès du médicament à la tumeur. C’est pourquoi, vouloir améliorer l’oxygénation et la perfusion tumorale, via entre autre la modulation du tonus et de l’endothélium vasculaires, la diminution de la pression interstitielle ou encore via l’hyperthermie, semble être une piste prometteuse pour améliorer l’accès du médicament à la tumeur.
quelques techniques déjà utilisées en clinique comme l’imagerie fonctionnelle ou encore l’angiographie via le CT-scan à l’iode permettent déjà de caractériser ces facteurs hémodynamiques/ mais au vu des résultats positifs des différents outils non invasifs développés dans ce mémoire, une application future en clinique semble être envisageable

Neoplasms --- Angiogenesis Modulating Agents --- Vascular Endothelial Growth Factor --- Chemotherapy --- Tumor Necrosis Factor-alpha

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Chemokine Receptors in Cancer summarizes the growing body of evidence that several chemokine receptors contribute to tumor behavior. Chemokine receptors were first identified on leukocytes and mediate directed migration of many host cells to sites of ligand expression. It is now well established that most malignant cells also express one or more chemokine receptor. This book describes our current understanding regarding how chemokine receptors contribute to tumor cell migration as well as cell survival and proliferation. The function of chemokine receptors expressed on host cells including antitumor immune effector cells as well as angiostatic and angiogeneic functions of chemokines acting on endothelial cells are described. The role of chemokine receptors that act as decoy receptors is also summarized. The therapeutic potential and challenges of targeting chemokine receptors or cognate ligands is also addressed.

Cancer cells --- Chemokines --- Receptors, Cytokine --- Antigens, CD --- Receptors, G-Protein-Coupled --- Diseases --- Angiogenesis Modulating Agents --- Growth Substances --- Receptors, Immunologic --- Antigens, Differentiation --- Receptors, Cell Surface --- Membrane Proteins --- Biological Markers --- Antigens, Surface --- Physiological Effects of Drugs --- Pharmacologic Actions --- Proteins --- Antigens --- Biological Factors --- Amino Acids, Peptides, and Proteins --- Chemicals and Drugs --- Chemical Actions and Uses --- Angiogenesis Inducing Agents --- Neoplasms --- Receptors, Chemokine --- Biology --- Health & Biological Sciences --- Medicine --- Pharmacy, Therapeutics, & Pharmacology --- Oncology --- Microbiology & Immunology --- Growth --- Regulation. --- Receptors --- Effect of drugs on. --- Effect of drugs on --- Regulation --- Chemokines. --- Drug receptors. --- Drugs --- Receptors, Drug --- Chemotactic cytokines --- Inflammatory peptides --- Intercrines --- Medicine. --- Cancer research. --- Oncology. --- Biomedicine. --- Cancer Research. --- Cell receptors --- Cytokines --- Inflammation --- Peptides --- Mediators --- Oncology  . --- Tumors --- Cancer research

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Tumour survival and growth is critically dependent on an independent blood supply. As such tumour vasculature presents an ideal target for cancer therapy that is widely applicable, accessible and genetically stable rendering it less prone to resistance. Two approaches have been explored for cancer therapy; firstly the prevention of new vessel formation with inhibitors of angiogenesis, and secondly the destruction of existing tumour blood vessels with so called vascular disruptive agents (VDAs). While the first approach appears to delay tumour progression, the second has the potential to cause massive cell death and tumour regression. It is the second approach of vascular targeting that is the focus of this book. Since the tubulin binding agent combretastatin, derived from the bark of the African bush willow, was discovered by George R Pettit to have antimitotic properties over twenty years ago, the field of vascular targeting has expanded steadily. Coincident with the preclinical and clinical development of these agents, there have been advances in our understanding of their mechanism of action and in the technology required to assess their effects. This book aims to provide a comprehensive account of the current state of the art. Preclinical target identification and validation are discussed and the optimum pre-clinical animal models described. The imaging modalities that can be used to assess the efficacy of these agents are examined and a comprehensive review of the clinical development of key drugs is provided. Finally, the recent research exploring rational combinations of VDAs with other agents is reviewed and the potential place of VDAs in the future of cancer therapy is critically appraised.

Cancer -- Chemotherapy. --- Drug targeting. --- Tumors -- Blood-vessels. --- Tumors --- Cancer --- Drug targeting --- Antineoplastic Agents --- Angiogenesis Modulating Agents --- Diseases --- Growth Inhibitors --- Therapeutics --- Growth Substances --- Therapeutic Uses --- Analytical, Diagnostic and Therapeutic Techniques and Equipment --- Angiogenesis Inhibitors --- Drug Therapy --- Drug Delivery Systems --- Neoplasms --- Physiological Effects of Drugs --- Pharmacologic Actions --- Chemical Actions and Uses --- Chemicals and Drugs --- Medicine --- Health & Biological Sciences --- Oncology --- Blood-vessels --- Chemotherapy --- Oncology. --- Treatment. --- Cancer therapy --- Cancer treatment --- Therapy --- Medicine. --- Cancer research. --- Pharmacology. --- Biomedicine. --- Cancer Research. --- Pharmacology/Toxicology. --- Drug effects --- Medical pharmacology --- Medical sciences --- Chemicals --- Drugs --- Pharmacy --- Cancer research --- Clinical sciences --- Medical profession --- Human biology --- Life sciences --- Pathology --- Physicians --- Physiological effect --- Toxicology. --- Pharmacology --- Poisoning --- Poisons --- Toxicology

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Angiogenesis is attracting increased scientific and clinical interest. The identification of novel mediators and targeting molecules has led to significant progress in our understanding of tumor angiogenesis and tumor vessel targeting. Important advances in cancer treatment have already emerged, and in the future, blood vessel targeting will play a significant role within individualized therapeutic strategies. This volume provides a general overview of the latest developments in angiogenesis inhibition in cancer. All aspects from the bench to the bedside are considered, with detailed attention both to basic research and to its translation into clinical practice. Individual chapters are devoted to the roles of angiopoietins, HIF-1a, chemokines, PDGF and VEGF, and vascular integrins. The latest results of clinical trials on therapeutic compounds are presented, and various advanced targeting strategies are discussed. This book will be invaluable to all who wish to learn of the most recent advances in research and treatment in this exciting field.

Angiogenesis Inhibitors. --- Neoplasms -- drug therapy. --- Neovascularization inhibitors. --- Neovascularization, Pathologic -- drug therapy. --- Neovascularization inhibitors --- Neoplasms --- Angiogenesis Inhibitors --- Drug Therapy --- Neovascularization, Pathologic --- Therapeutics --- Diseases --- Angiogenesis Modulating Agents --- Metaplasia --- Antineoplastic Agents --- Growth Inhibitors --- Therapeutic Uses --- Growth Substances --- Pathologic Processes --- Analytical, Diagnostic and Therapeutic Techniques and Equipment --- Pharmacologic Actions --- Physiological Effects of Drugs --- Pathological Conditions, Signs and Symptoms --- Chemical Actions and Uses --- Chemicals and Drugs --- Oncology --- Medicine --- Health & Biological Sciences --- Cancer --- Therapeutic use. --- Chemotherapy. --- Angiogenesis inhibitors --- Tumor angiogenesis inhibitors --- Medicine. --- Cancer research. --- Hematology. --- Oncology. --- Medicine & Public Health. --- Cancer Research. --- Tumors --- Haematology --- Internal medicine --- Blood --- Cancer research --- Clinical sciences --- Medical profession --- Human biology --- Life sciences --- Medical sciences --- Pathology --- Physicians --- Antineoplastic agents --- Treatment