RESUMO
Many pathological conditions are characterized or caused by the presence of an insufficient or aberrant local vasculature. Thus, therapeutic approaches aimed at modulating the caliber and/or density of the vasculature by controlling angiogenesis and arteriogenesis have been under development for many years. As our understanding of the underlying cellular and molecular mechanisms of these vascular growth processes continues to grow, so too do the available targets for therapeutic intervention. Nonetheless, the tools needed to implement such therapies have often had inherent weaknesses (i.e., invasiveness, expense, poor targeting, and control) that preclude successful outcomes. Approximately 20 years ago, the potential for using ultrasound as a new tool for therapeutically manipulating angiogenesis and arteriogenesis began to emerge. Indeed, the ability of ultrasound, especially when used in combination with contrast agent microbubbles, to mechanically manipulate the microvasculature has opened several doors for exploration. In turn, multiple studies on the influence of ultrasound-mediated bioeffects on vascular growth and the use of ultrasound for the targeted stimulation of blood vessel growth via drug and gene delivery have been performed and published over the years. In this review article, we first discuss the basic principles of therapeutic ultrasound for stimulating angiogenesis and arteriogenesis. We then follow this with a comprehensive cataloging of studies that have used ultrasound for stimulating revascularization to date. Finally, we offer a brief perspective on the future of such approaches, in the context of both further research development and possible clinical translation.
Assuntos
Neovascularização Fisiológica/efeitos da radiação , Ondas Ultrassônicas , Remodelação Vascular/efeitos da radiação , Indutores da Angiogênese/administração & dosagem , Indutores da Angiogênese/metabolismo , Animais , Materiais Biocompatíveis , Biomarcadores , Meios de Contraste , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Humanos , Microbolhas , Neovascularização Patológica/terapia , Terapia por Ultrassom/métodosRESUMO
The tumor microenvironment regulates cancer initiation, progression and response to treatment. In particular, the immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. We and others have shown that radiation therapy (RT) induces pericyte recruitment, resembling vascular normalization. Here, we asked whether radiation-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy. First, RT induced vascular remodeling, accompanied by decreased hypoxia and/or increased Hoechst perfusion in prostate PC3 and LNCaP and Lewis lung carcinoma. These results were independent of the RT regimen, respectively 10â¯×â¯2â¯Gy and 2â¯×â¯12â¯Gy, suggesting a common effect. Next, using doxorubicin as a fluorescent reporter, we observed that RT improves intra-tumoral chemotherapy distribution. These effects were not hindered by anti-angiogenic sunitinib. Moreover, sub-optimal doses of doxorubicin had almost no effect alone, but significantly delayed tumor growth after RT. These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution, and could be an alternative chemosensitizing strategy.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma Pulmonar de Lewis/irrigação sanguínea , Carcinoma Pulmonar de Lewis/terapia , Quimiorradioterapia , Doxorrubicina/farmacologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/terapia , Doses de Radiação , Remodelação Vascular/efeitos da radiação , Animais , Antibióticos Antineoplásicos/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Doxorrubicina/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Neovascularização Patológica , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Hipóxia Tumoral , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND AND PURPOSE: In thoracic irradiation, the maximum radiation dose is restricted by the risk of radiation-induced cardiopulmonary damage and dysfunction limiting tumor control. We showed that radiation-induced sub-clinical cardiac damage and lung damage in rats mutually interact and that combined irradiation intensifies cardiopulmonary toxicity. Unfortunately, current clinical practice does not include preventative measures to attenuate radiation-induced lung or cardiac toxicity. Here, we investigate the effects of the ACE inhibitor captopril on radiation-induced cardiopulmonary damage. MATERIAL AND METHODS: After local irradiation of rat heart and/or lungs captopril was administered orally. Cardiopulmonary performance was assessed using biweekly breathing rate measurements. At 8 weeks post-irradiation, cardiac hemodynamics were measured, CT scans and histopathology were analyzed. RESULTS: Captopril significantly improved breathing rate and cardiopulmonary density/structure, but only when the heart was included in the radiation field. Consistently, captopril reduced radiation-induced pleural and pericardial effusion and cardiac fibrosis, resulting in an improved left ventricular end-diastolic pressure only in the heart-irradiated groups. CONCLUSION: Captopril improves cardiopulmonary morphology and function by reducing acute cardiac damage, a risk factor in the development of radiation-induced cardiopulmonary toxicity. ACE inhibition should be evaluated as a strategy to reduce cardiopulmonary complications induced by radiotherapy to the thoracic area.