RESUMO
The pathogenic mechanism of nicotine, a major product of smoking, on vascular endothelial cells is not well defined yet. The purpose of this study was to determine whether chronic exposure to nicotine alters angiogenic activity in human umbilical vein endothelial cells and to identify a potential role for endothelial nitric oxide synthase (eNOS) expression. Our study demonstrated that acute nicotine treatment enhanced nitric oxide release, eNOS activation, and proangiogenic activity. However, chronic nicotine exposure impaired proangiogenic function (decreased cell migration and tubular structure formation) in human umbilical vein endothelial cells compared with acute exposure, but sustained the antiapoptotic effect. These findings seem to be related to eNOS gene expression and nitric oxide production, which may be involved in the pathophysiology of chronic nicotine addicts.
Assuntos
Moduladores da Angiogênese/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Nicotina/efeitos adversos , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Moduladores da Angiogênese/administração & dosagem , Apoptose/efeitos dos fármacos , Ensaios de Migração Celular , Células Cultivadas , Células Endoteliais/citologia , Endotélio Vascular/metabolismo , Expressão Gênica , Humanos , Nicotina/administração & dosagem , Óxido Nítrico/análise , Óxido Nítrico/biossíntese , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/fisiologia , Fumaça , Nicotiana , Veias Umbilicais/citologia , Veias Umbilicais/efeitos dos fármacos , Veias Umbilicais/fisiologiaRESUMO
BACKGROUND: Molecular targeted therapy increased overall and disease-free survival in a wide range of malignancies. Although generally well tolerated compared to chemotherapy, molecular targeted therapy may be associated with adverse events requiring ICU admission. Informing clinicians about clinical features of these toxic events might maintain awareness and favor early recognition, prompt diagnosis and treatment. METHODS: We performed a systematic review of published case reports of molecular targeted therapy-related life-threatening toxicity that led to ICU admission. The search used the Pubmed database using medical subject heading (Mesh) terms, including all FDA-approved molecular targeted therapy (TT), up to March 2019. No language restriction was applied. All cases reports of patients admitted to the ICU for molecular targeted therapy-related toxicity were included. Non-FDA-approved combinations of treatments or hormonal therapy were not included. RESULTS: Two hundred and fifty-three cases were identified. Nearly half of them (n = 102; 40.3%) were related to anti-angiogenic agents, mostly for gastrointestinal and cardiovascular complications. Other molecules responsible for adverse events were chiefly immune checkpoint inhibitors (n = 85, 33.6%), EGFR inhibitors (n = 33; 13.0%), and anti-HER2 (n = 10; 4.0%). They were associated with adverse events such as respiratory or hypersensitivity events. Management and outcomes associated with these life-threatening complications are reported. CONCLUSIONS: Based on the vast number of treated patients, only 253 cases of molecular therapy-related severe toxicity are reported in cancer patients. Symptoms and biomarkers that depict these events need to be better identified as to allow appropriate reporting and improving dose and schedule of the treatment adapted to each patient.
Assuntos
Unidades de Terapia Intensiva , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Moduladores da Angiogênese/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/terapia , Hipersensibilidade a Drogas/terapia , Receptores ErbB/antagonistas & inibidores , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/terapia , Humanos , Fatores Imunológicos/efeitos adversos , Receptor ErbB-2/antagonistas & inibidores , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/terapia , Índice de Gravidade de DoençaRESUMO
Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy.
Assuntos
Moduladores da Angiogênese/efeitos adversos , Neoplasias/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Tromboembolia/induzido quimicamente , Anticoagulantes/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neovascularização Patológica/fisiopatologia , Tromboembolia/fisiopatologia , Tromboembolia/prevenção & controleRESUMO
PURPOSE: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. METHODS AND MATERIALS: Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, and 40 weeks after irradiation. RESULTS: Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. CONCLUSIONS: Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.
Assuntos
Moduladores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Túbulos Renais/efeitos dos fármacos , Rim/efeitos da radiação , Lesões Experimentais por Radiação/prevenção & controle , Talidomida/farmacologia , Moduladores da Angiogênese/efeitos adversos , Animais , Anti-Inflamatórios/efeitos adversos , Feminino , Fibrose , Genes sis/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos da radiação , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/patologia , Túbulos Renais/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Nefrite/patologia , Nefrite/prevenção & controle , Talidomida/efeitos adversosRESUMO
Resveratrol, a natural polyphenol produced by plants in response to environmental stress, has received great attention during the past few years due to its beneficial roles in longevity and glucose homeostasis. Resveratrol has been found to display antioxidant, anti-inflammatory, antifibrotic, and cardioprotective properties. Resveratrol reduces platelet aggregation, induces vasorelaxation, limits endothelial activation, and modulates lipid and lipoprotein metabolism. Although the mechanisms of action of resveratrol have not been completely defined, there is evidence that some of the effects of resveratrol may be mediated via activation of sirtuin 1 and AMP-activated protein kinase and through inhibition of the pleiotropic transcription factor nuclear factor κB. Pathways proposed to underlie resveratrol-mediated cardioprotection include reduction of oxidative stress and activation of endothelial nitric oxide synthase. Adenosinergic mechanisms may play a role in its atheroprotective activity. The ability of the nutraceutical resveratrol to positively influence the future treatment of cardiovascular disease is discussed.