Les antiangiogéniques (AAD) représentent une classe relativement récente d’anticancéreux indiqués dans un nombre croissant de cancers solides avancés. Ces traitements inhibent la voie du VEGF en amont avec le bevacizumab, un anticorps monoclonal dirigé contre le VEGF et en aval avec les inhibiteurs des tyrosines kinases des récepteurs impliqués dans cette voie de signalisation (sorafenib et sunitinib). Les AAD s’accompagnent d’effets secondaires dont le plus fréquent est l’hypertension artérielle. Ma thèse a pour objectif de mieux comprendre la physiopathologie de l’hypertension artérielle iatrogène induite par les AAD, notamment en mesurant l’effet des AAD sur les grosses artères. Le deuxième objectif est de déterminer des marqueurs précoces d’efficacité et d’optimisation de ces traitements, notamment avec un suivi thérapeutique pharmacologique (STP). Pour remplir ces objectifs nous avons mis en place une étude clinique prospective, observationnelle monocentrique dans laquelle nous avons suivi l’évolution de paramètres artériels au cours du traitement AAD avec des techniques non-invasives chez des patients atteints d’un cancer. Dans un premier travail nous avons montré qu’il y avait une augmentation précoce et cliniquement significative de la pression brachiale et centrale, de la rigidité artérielle et du diamètre carotidien sous AAD et que ces modifications étaient en partie indépendantes de la pression artérielle. Nous avons également montré que la présence d’ondes de réflexion amples et d’une rigidité aortique basse de base avant l’introduction des AAD prédisaient une augmentation de pression artérielle systolique (PAS) à un stade précoce d’exposition (coefficients de régression : 0.37[0.04-0.70] et -1.27[-2.43 ; -0.11], p<0.05 respectivement) alors qu’après une exposition chronique aux AAD, seule une rigidité artérielle basse de base prédisait une augmentation de la PAS (-2.46 [-4.02 ; -0.90], p<0.01). L’atteinte des grosses artères est positivement associée à l’évolution carcinologique. En effet une augmentation précoce de la rigidité aortique et carotidienne sous AAD étaient associées à un haut risque de progression (HR : 1.24 [1.01 ; 1.51], p=0.042 et 1.34 [1.03-1.73], p=0.027 respectivement). Dans la deuxième partie, nous avons montré à l’aide d’un modèle pharmacocinétique de population, que l’atteinte artérielle observée lors de la prise d’AAD était due à un effet pharmacologique des AAD sur les grosses artères indépendamment de l’augmentation de pression induite par les AAD. L’augmentation de rigidité artérielle était proportionnelle à la concentration plasmatique d’AAD et à l’augmentation de la pression artérielle (coefficient de corrélation standardisé : 0.37 et 0.35, p<0.01, respectivement), expliquant respectivement 13% et 11% de la variance. Nous avons également montré que la progression et la mortalité liées au cancer étaient moindre chez les patients les plus exposés aux AAD (HR : 0.60 [0.38 ; 0.97], p=0.035 et HR=0.38 [0.19-0.79], P=0.01 respectivement) et enfin, nous avons pu déterminer une concentration sérique cible qui permettra aux cliniciens d’avoir un objectif à atteindre pour optimiser l’efficacité des AAD. En conclusion, nous avons pu démontrer l’existence d’une atteinte précoce des grosses artères se traduisant par une augmentation de la rigidité artérielle et un remodelage carotidien sous traitement AAD. Cette atteinte artérielle est directement liée à un effet pharmacologique des AAD de manière indépendante de l’augmentation de pression induite par ces traitements. Nous avons montré que les altérations de la paroi artérielle ainsi que le suivi thérapeutique pharmacologique prédisaient le pronostic carcinologique. Le suivi des propriétés artérielles combinée au STP des AAD pourraient optimiser les chances d’efficacité de ces traitements. / Antiangiogenic drugs (AAD) are a relatively new class of anti-cancer therapy indicated in an increasing number of advanced solid tumors. By inhibiting the VEGF pathway, upstream with an anti-VEGF monoclonal antibody, bévacizumab, and downstream with tyrosine kinase inhibitors of receptors involved in this signaling pathway (sorafenib and sunitinib), AAD induce arterial hypertension which is the most common side effect. The principal objective of my thesis is to improve the understanding of the pathophysiology of hypertension induced by AAD, by determining the effect of AAD on large arteries. The second objective is to determine early marker of efficacy and optimization of AAD, by the use of therapeutic drug monitoring. To fulfill those objectives, we set up a clinical prospective, observational, single center study in which we followed the time-course of several arterial parameters after AAD by the use of non-invasive techniques in patients with metastatic solid tumors. In a first work we showed that brachial and central blood pressure, arterial stiffness and carotid diameter significantly increased after AAD, partly independently of blood pressure changes. We also showed that high reflection waves and low aortic stiffness at baseline (i.e. before AAD initiation) predicted early systolic blood pressure (SBP) increase (regression coefficients: 0.37[0.04; 0.70] and -1.27[-2.43; -0.11], P<0.05 respectively) while only low aortic stiffness predicted SBP increase after chronic AAD exposure (-2.46 [-4.02 ; -0.90], P<0.01). Large arteries damage under AAD is positively associated with cancer progression. Indeed, early increase of aortic and carotid stiffness after AAD were associated with a higher risk of cancer progression (HR: 1.24 [1.01; 1.51], P=0.042 and 1.34 [1.03; 1.73], P=0.027 respectively). In a second part, using a pharmacokinetic model of population, we showed that large arteries damage observed after AAD was partly due to a pharmacological effect of AAD on large arteries independently of blood pressure increase. Arterial stiffness increase was proportional to AAD blood concentration and blood pressure increase (standardized correlation coefficients: 0.37 and 0.35, P<0.01, respectively), explaining 13% and 11% of the variance respectively. We also showed that progression and mortality related to cancer were lower in patients high AAD blood concentrations (HR: 0.60 [0.38; 0.97], P=0.035 and HR=0.38 [0.19; 0.79], P=0.01 respectively). And finally, we determined a target AAD blood concentration which will allow the clinicians to have an objective to reach in order to optimize the efficacy of AAD. In conclusion, we were able to demonstrate the existence of large arteries damage translated by large arteries stiffening and a remodeling of carotid artery after AAD. This arterial damage is directly related to a pharmacological effect of AAD independently of blood pressure changes induced by these treatments. We showed that infringement of the arterial wall and the therapeutic drug monitoring predicted tumor prognosis. Thus, the monitoring of arterial properties monitoring and the therapeutic drug monitoring might optimize the chances of efficiency of AAD.

Made available in DSpace on 2014-07-29T15:25:22Z (GMT). No. of bitstreams: 1 tese joao arraes ciencias saude.pdf: 3252483 bytes, checksum: be116024cf6d2b2b6cef094fc736420d (MD5) Previous issue date: 2009-06-19 / Antiangiogenesis therapy has become a first-line treatment for neovascular age-related macular degeneration (AMD). Bevacizumab has proven to be efficient and cost effective, however its use in AMD is still off-label. PURPOSES: Evaluating the histological toxicity of bevacizumab on the neurosensorial retina (NSR) and the retinal pigmented epithelium (RPE) in pigmented rabbit eyes; evaluating if a fast increase in vitreous volume after a 0.1 ml balanced saline solution (BSS) intravitreal injection (IVI) in a rabbit eye will lead to histological damages in the NSR and RPE; and evaluating postoperative clinical complications after an IVI in rabbits eyes. METHODS: Eighteen pigmented rabbits (36 eyes) were divided into 4 groups a Control Group (3 rabbits - 6 eyes), which did not receive any IVI; the rabbits were sacrificed at the beginning of the study. Thirty eyes of the fifteen remaining rabbits were distributed to three groups: a sham group (S), that received a 0.1 ml balanced saline solution (BSS) IVI (ten eyes); group 1, that received a 1.25 mg (0.1 ml) bevacizumab IVI (ten eyes); and group 2, that received a 2.5 mg (0.1 ml) bevacizumab IVI (ten eyes). Postoperative clinical evaluation included inspection of the anterior segment and indirect binocular ophthalmoscopy. The rabbits were sacrificed 90 days after the procedure and both eyes of all the rabbits were enucleated. Histological examination of the NSR and RPE were performed and their morphological features and layer thickness were analyzed. RESULTS: No significant postoperative clinical complications were observed either in the neurossensorial retina or in the RPE. Histological morphology and thickness of the NSR and RPE layers did not differ significantly between BBS-injected eyes and bevacizumab-injected eyes. CONCLUSIONS: A rapid increase in vitreous volume, after 0.1 ml BSS IVI did not lead to any histological damage in the NSR and RPE in rabbit eyes. After a 90-day follow-up period, a single Bevacizumab 1.25 and 2.5 mg intravitreal injection did not lead any toxic damage in the NSR and RPE. No important postoperative complications in pigmented rabbit eyes were observed and it appears to be a safe procedure for the treatment of retinal neovascular diseases / A terapia anti-angiogênica tornou-se o tratamento de primeira linha para a forma neovascular da degeneração macular relacionada à idade. O Bevacizumabe é uma droga com boa eficácia e custo-efetividade, porém seu uso nesta doença ainda é considerado off-label. OBJETIVOS: Avaliar a toxicidade sobre a retina neurossensorial (RNS) e epitélio pigmentado da retina (EPR) da injeção intra-vítrea (IV) de bevacizumabe em olhos de coelhos não albinos; avaliar se o aumento súbito do volume vítreo após a injeção IV de 0,1ml de solução salina balanceada (SSB) no olho do coelho leva a danos histológicos na RNS e EPR; e avaliar as complicações clínicas pós-operatórias após a injeção IV em olhos de coelhos. MÉTODOS: 18 coelhos não albinos (36 olhos) foram distribuídos em 4 grupos. O grupo controle (3 coelhos 6 olhos), o qual não recebeu injeção IV, foi sacrificado no início do estudo. Os trinta olhos dos 15 coelhos restantes foram distribuídos em 3 grupos (1:1:1): Grupo Placebo (injeção IV de 0,1ml de SSB); Grupo 1 (injeção IV de 1,25mg/0,1ml de bevacizumabe); e Grupo 2 (injeção IV de 2,5mg/0,1ml de bevacizumabe). Os coelhos foram acompanhados por um período de 90 dias após o procedimento, quando então foram submetidos a eutanásia. Todos os coelhos tiveram seus olhos enucleados e avaliados histologicamente. Foram realizadas avaliação clínica pós-operatória (inspeção do segmento anterior e oftalmoscopia binocular indireta) e avaliação histológica da morfologia e da espessura das camadas da RNS e EPR. RESULTADOS: Não foram observadas complicações clínicas pós-operatórias significantes. A morfologia histológica e espessura das camadas da RNS e EPR não apresentou diferença significante entre os grupos controle e placebo, grupo placebo e grupo 1 e grupo placebo e grupo 2. CONCLUSÕES: A injeção IV de 1,25mg/0,1ml e 2,5mg/0,1ml bevacizumabe não leva a alterações histológicas tóxicas na RNS e EPR, nem a complicações clínicas pós-operatórias importantes em olhos de coelhos não albinos. A injeção IV de 0,1ml de SSB não leva a danos histológicos ao RNS e ao EPR em olhos de coelhos não albinos