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2.
JAAPA ; 34(12): 1, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34813567

Assuntos
COVID-19 , Humanos , SARS-CoV-2
3.
J Clin Invest ; 129(7): 2964-2979, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31205032

RESUMO

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 (TXA2) pathway. Preoperative stimulation of inflammation resolution via resolvins (RvD2, RvD3, and RvD4) inhibited metastases and induced T cell responses. Ketorolac and resolvins exhibited synergistic antitumor activity and prevented surgery- or chemotherapy-induced dormancy escape. Thus, simultaneously blocking the ensuing proinflammatory response and activating endogenous resolution programs before surgery may eliminate micrometastases and reduce tumor recurrence.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Imunidade Celular/efeitos dos fármacos , Cetorolaco/farmacologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias Experimentais , Cuidados Pré-Operatórios , Linfócitos T/metabolismo , Animais , Masculino , Camundongos , Camundongos Knockout , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Linfócitos T/patologia
4.
J Exp Med ; 215(1): 115-140, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29191914

RESUMO

Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Thus, conventional cancer therapy is inherently a double-edged sword. In this study, we show that tumor cells killed by chemotherapy or targeted therapy ("tumor cell debris") stimulate primary tumor growth when coinjected with a subthreshold (nontumorigenic) inoculum of tumor cells by triggering macrophage proinflammatory cytokine release after phosphatidylserine exposure. Debris-stimulated tumors were inhibited by antiinflammatory and proresolving lipid autacoids, namely resolvin D1 (RvD1), RvD2, or RvE1. These mediators specifically inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumor types. Resolvins counterregulate the release of cytokines/chemokines, including TNFα, IL-6, IL-8, CCL4, and CCL5, by human macrophages stimulated with cell debris. These results demonstrate that enhancing endogenous clearance of tumor cell debris is a new therapeutic target that may complement cytotoxic cancer therapies.


Assuntos
Antineoplásicos/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Melanoma Experimental , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Fagocitose , Fosfatidilserinas/metabolismo , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
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