Bevacizumab-induced hypertension: Clinical presentation and molecular understanding

Li, Megan; Kroetz, Deanna L.

doi:10.1016/j.pharmthera.2017.08.012

Cited by 108 publications

(95 citation statements)

References 124 publications

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“…Therefore, we studied plasma and lung specimens from patients treated with bevacizumab, a humanized monoclonal antibody directed against VEGF. Cardiovascular side-effects of bevacizumab include thromboembolic events [22,41], ischemic events [10,41], hypertension [16,28,55], pulmonary embolism [22,39,41] and pulmonary hypertension [29]. The mechanism of these bevacizumab-related cardiovascular events is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension

et al. 2020

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Pulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the kinase insert domain protein receptor (kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr ∆end) and held them in an environmental chamber with 10% FiO 2 or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr ∆end mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3 + endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of Kdr. Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.

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Section: Discussionmentioning

confidence: 99%

Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension

et al. 2020

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“…Subsequently it has been approved as part of a combination therapy in the treatment of various cancers, including metastatic lung, colorectal, and renal cell carcinoma, and as a single agent treatment in adult glioblastoma [37]. However, subsequent studies have revealed adverse effects, including gastrointestinal perforation, nephrotic syndrome, thromboembolism, surgical wound healing complications and hypertension [37,38].…”

Section: Introductionmentioning

confidence: 99%

Targeting Angiogenesis in Prostate Cancer

Melegh

Oltean

2019

IJMS

101

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Prostate cancer is the most commonly diagnosed cancer among men in the Western world. Although localized disease can be effectively treated with established surgical and radiopharmaceutical treatments options, the prognosis of castration-resistant advanced prostate cancer is still disappointing. The objective of this study was to review the role of angiogenesis in prostate cancer and to investigate the effectiveness of anti-angiogenic therapies. A literature search of clinical trials testing the efficacy of anti-angiogenic therapy in prostate cancer was performed using Pubmed. Surrogate markers of angiogenic activity (microvessel density and vascular endothelial growth factor A (VEGF-A) expression) were found to be associated with tumor grade, metastasis, and prognosis. Six randomizedstudies were included in this review: two phase II trials on localized and hormone-sensitive disease (n = 60 and 99 patients) and four phase III trials on castration-resistant refractory disease (n = 873 to 1224 patients). Although the phase II trials showed improved relapse-free survival and stabilisation of the disease, the phase III trials found increased toxicity and no significant improvement in overall survival. Although angiogenesis appears to have an important role in prostate cancer, the results of anti-angiogenic therapy in castration-resistant refractory disease have hitherto been disappointing. There are various possible explanations for this lack of efficacy in castration-resistant refractory disease: redundancy of angiogenic pathways, molecular heterogeneity of the disease, loss of tumor suppressor protein phosphatase and tensin homolog (PTEN) expression as well as various VEGF-A splicing isoforms with pro- and anti-angiogenic activity. A better understanding of the molecular mechanisms of angiogenesis may help to develop effective anti-angiogenic therapy in prostate cancer.

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“…Quanto à hipertensão arterial, alguns quimioterápicos estão diretamente relacionados ao desenvolvimento ou piora da hipertensão pré-existente, por exemplo, os inibidores do fator angiogênico (anti-VEGF), como o Bevacizumabe [32][33] . Este anticorpo monoclonal é indicado, atualmente, como primeira linha do tratamento do câncer colorretal mestastático [32][33] e as taxas de hipertensão associadas ao uso deste quimioterápico vão de 4% a 35% dos pacientes 34 . Dado o seu mecanismo de ação, ocorre vasoconstrição sistêmica, com consequente ativação do sistema renina-angiotensina-aldosterona e desenvolvimento e/ou complicação da hipertensão arterial 32,34 .…”

Section: Discussionunclassified

Sobrevida de pacientes com neoplasia maligna de colo conforme localização primária à direita ou esquerda

França¹,

Bertolazzi²

2019

ACS

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Introdução. As neoplasias de colo possuem relevância epidemiológica mundial. Dada sua heterogeneidade molecular e clínica, o diagnóstico em estádios iniciais e tratamento precoce tornam-se essenciais para ganho de sobrevida. Outro fator determinante para a sobrevida e predição do desfecho dessas neoplasias diz respeito à localização primária da doença, destacando-se suas lateralidades. Objetivos. Investigar associação entre taxas de sobrevida e a localização à direita ou esquerda das neoplasias de colo. Métodos. Trata-se de estudo transversal com delineamento descritivo, abordagem quantitativa do tipo analítica, com correlação entre variáveis. Foram sujeitos do estudo pacientes atendidos em complexo hospitalar quaternário no interior de São Paulo entre 2010 e 2017. A coleta de dados aconteceu de forma retrospectiva e documental, a partir de fontes do Registro Hospitalar de Câncer e prontuários informatizados. Os dados sociodemográficos, clínico-patológicos e de sobrevida foram analisados pelo programa IBM SPSS Statistical Package v.25 (IBM Corporation) e apresentados em mediana, interquartis e curva de Kaplan Meier, conforme natureza dessas variáveis. Resultados. A amostra final de 691 pacientes teve maioria diagnosticada com neoplasias de colo esquerdo (n=392;56,7%), especialmente sigmoide (n=282;40,9%), com discreta predominância de homens (n=351;50,8%) e entre os estádios II (n=193;27,9%) e III (n=213;30,9%). Os adenocarcinomas tubulares foram o tipo morfológico mais frequente (n=477;69%). A idade variou de 14 a 97 (Mediana 63,7) anos. A maior parte dos pacientes se declararam brancos (n=623;90,2%) e proveniente das cidades do Departamento Regional de Saúde XV (n=408;59%). Ocorreram 296 (42,8%) óbitos no período, especialmente em portadores de neoplasia de colo à direita (n=149; 50,3%). O tempo de sobrevida global teve mediana de 807 dias (interquartil 25= 284; interquartil 75=1622), sendo de 866 dias para colo à esquerda e 675 dias para colo à direita. Conclusão. As neoplasias de colo direito podem ser vistas como possível preditor independente de óbito (sobrevida de 1,8 anos) quando comparadas com neoplasias de colo à esquerda (sobrevida de 2,4 anos).

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Bevacizumab-induced hypertension: Clinical presentation and molecular understanding

Cited by 108 publications

References 124 publications

Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension

Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension

Targeting Angiogenesis in Prostate Cancer

Sobrevida de pacientes com neoplasia maligna de colo conforme localização primária à direita ou esquerda

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