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1.
Immunity ; 49(3): 490-503.e4, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30170810

RESUMO

The NF-κB pathway plays a crucial role in supporting tumor initiation, progression, and radioresistance of tumor cells. However, the role of the NF-κB pathway in radiation-induced anti-tumor host immunity remains unclear. Here we demonstrated that inhibiting the canonical NF-κB pathway dampened the therapeutic effect of ionizing radiation (IR), whereas non-canonical NF-κB deficiency promoted IR-induced anti-tumor immunity. Mechanistic studies revealed that non-canonical NF-κB signaling in dendritic cells (DCs) was activated by the STING sensor-dependent DNA-sensing pathway. By suppressing recruitment of the transcription factor RelA onto the Ifnb promoter, activation of the non-canonical NF-κB pathway resulted in decreased type I IFN expression. Administration of a specific inhibitor of the non-canonical NF-κB pathway enhanced the anti-tumor effect of IR in murine models. These findings reveal the potentially interactive roles for canonical and non-canonical NF-κB pathways in IR-induced STING-IFN production and provide an alternative strategy to improve cancer radiotherapy.


Assuntos
Neoplasias do Colo/radioterapia , Células Dendríticas/imunologia , Melanoma/radioterapia , NF-kappa B/metabolismo , Neoplasias Experimentais/radioterapia , Radioterapia/métodos , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Neoplasias do Colo/imunologia , DNA/imunologia , Modelos Animais de Doenças , Humanos , Imunidade Celular , Melanoma/imunologia , Melanoma Experimental , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Tolerância a Radiação , Radiação Ionizante , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Immunity ; 41(5): 843-52, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25517616

RESUMO

Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-? induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation-induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-? treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA-sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy.


Assuntos
DNA/imunologia , Proteínas de Membrana/genética , Neoplasias/radioterapia , Nucleotidiltransferases/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Antineoplásicos/farmacologia , Células Cultivadas , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Imunidade Inata , Interferon beta/biossíntese , Interferon beta/imunologia , Interferon beta/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Neoplasias/imunologia , Nucleotídeos Cíclicos/farmacologia , Interferência de RNA , RNA Interferente Pequeno , Radiação Ionizante , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais/imunologia , Xantonas/farmacologia
3.
Mol Ther ; 20(5): 1046-55, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22334019

RESUMO

Radiotherapy offers an effective treatment for advanced cancer but local and distant failures remain a significant challenge. Here, we treated melanoma and pancreatic carcinoma in syngeneic mice with ionizing radiation (IR) combined with the poly(ADP-ribose) polymerase inhibitor (PARPi) veliparib to inhibit DNA repair and promote accelerated senescence. Based on prior work implicating cytotoxic T lymphocytes (CTLs) as key mediators of radiation effects, we discovered that senescent tumor cells induced by radiation and veliparib express immunostimulatory cytokines to activate CTLs that mediate an effective antitumor response. When these senescent tumor cells were injected into tumor-bearing mice, an antitumor CTL response was induced which potentiated the effects of radiation, resulting in elimination of established tumors. Applied to human cancers, radiation-inducible immunotherapy may enhance radiotherapy responses to prevent local recurrence and distant metastasis.


Assuntos
Benzimidazóis/farmacologia , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Melanoma Experimental/terapia , Neoplasias Pancreáticas/terapia , Radiossensibilizantes/farmacologia , Animais , Vacinas Anticâncer/imunologia , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Terapia Combinada , Citocinas/biossíntese , Citocinas/imunologia , Citotoxicidade Imunológica , Feminino , Humanos , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/mortalidade , Camundongos , Transplante de Neoplasias , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases , Taxa de Sobrevida , Linfócitos T Citotóxicos/imunologia , Células Tumorais Cultivadas
4.
Am J Respir Cell Mol Biol ; 44(3): 415-22, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20508068

RESUMO

Novel therapies are desperately needed for radiation-induced lung injury (RILI), which, despite aggressive corticosteroid therapy, remains a potentially fatal and dose-limiting complication of thoracic radiotherapy. We assessed the utility of simvastatin, an anti-inflammatory and lung barrier-protective agent, in a dose- and time-dependent murine model of RILI (18-(25 Gy). Simvastatin reduced multiple RILI indices, including vascular leak, leukocyte infiltration, and histological evidence of oxidative stress, while reversing RILI-associated dysregulated gene expression, including p53, nuclear factor-erythroid-2-related factor, and sphingolipid metabolic pathway genes. To identify key regulators of simvastatin-mediated RILI protection, we integrated whole-lung gene expression data obtained from radiated and simvastatin-treated mice with protein-protein interaction network analysis (single-network analysis of proteins). Topological analysis of the gene product interaction network identified eight top-prioritized genes (Ccna2a, Cdc2, fcer1 g, Syk, Vav3, Mmp9, Itgam, Cd44) as regulatory nodes within an activated RILI network. These studies identify the involvement of specific genes and gene networks in RILI pathobiology, and confirm that statins represent a novel strategy to limit RILI.


Assuntos
Regulação da Expressão Gênica , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lesão Pulmonar/metabolismo , Pulmão/metabolismo , Pulmão/efeitos da radiação , Lesões por Radiação/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Lavagem Broncoalveolar , Receptores de Hialuronatos/biossíntese , Lesão Pulmonar/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Mapeamento de Interação de Proteínas , Pneumonite por Radiação , Transcrição Gênica
5.
Mol Ther ; 18(5): 912-20, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20197756

RESUMO

Ad.Egr-TNF is a radioinducible adenovector currently in phase 3 trials for inoperable pancreatic cancer. The combination of Ad.Egr-TNF and ionizing radiation (IR) contributes to local tumor control through the production of tumor necrosis factor-alpha (TNFalpha) in the tumor microenvironment. Moreover, clinical and preclinical studies with Ad.Egr-TNF/IR have suggested that this local approach suppresses the growth of distant metastatic disease; however, the mechanisms responsible for this effect remain unclear. These studies have been performed in wild-type (WT) and TNFR1,2(-/-) mice to assess the role of TNFalpha-induced signaling in the suppression of draining lymph node (DLN) metastases. The results demonstrate that production of TNFalpha in the tumor microenvironment induces expression of interferon (IFNbeta). In turn, IFNbeta stimulates the production of chemokines that recruit CD8(+) T cells to the tumor. The results further demonstrate that activation of tumor antigen-specific CD8(+) CTLs contributes to local antitumor activity and suppression of DLN metastases. These findings support a model in which treatment of tumors with Ad.Egr-TNF and IR is mediated by local and distant immune-mediated antitumor effects that suppress the development of metastases.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Metástase Neoplásica/prevenção & controle , Metástase Neoplásica/terapia , Radiação Ionizante , Fator de Necrose Tumoral alfa/metabolismo , Adenoviridae/genética , Animais , Proliferação de Células , Vetores Genéticos/genética , Humanos , Interferon beta/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Metástase Neoplásica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/genética
6.
Am J Physiol Gastrointest Liver Physiol ; 297(6): G1041-52, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19833862

RESUMO

Intestinal injury following abdominal radiation therapy or accidental exposure remains a significant clinical problem that can result in varying degrees of mucosal destruction such as ulceration, vascular sclerosis, intestinal wall fibrosis, loss of barrier function, and even lethal gut-derived sepsis. We determined the ability of a high-molecular-weight polyethylene glycol-based copolymer, PEG 15-20, to protect the intestine against the early and late effects of radiation in mice and rats and to determine its mechanism of action by examining cultured rat intestinal epithelia. Rats were exposed to fractionated radiation in an established model of intestinal injury, whereby an intestinal segment is surgically placed into the scrotum and radiated daily. Radiation injury score was decreased in a dose-dependent manner in rats gavaged with 0.5 or 2.0 g/kg per day of PEG 15-20 (n = 9-13/group, P < 0.005). Complementary studies were performed in a novel mouse model of abdominal radiation followed by intestinal inoculation with Pseudomonas aeruginosa (P. aeruginosa), a common pathogen that causes lethal gut-derived sepsis following radiation. Mice mortality was decreased by 40% in mice drinking 1% PEG 15-20 (n = 10/group, P < 0.001). Parallel studies were performed in cultured rat intestinal epithelial cells treated with PEG 15-20 before radiation. Results demonstrated that PEG 15-20 prevented radiation-induced intestinal injury in rats, prevented apoptosis and lethal sepsis attributable to P. aeruginosa in mice, and protected cultured intestinal epithelial cells from apoptosis and microbial adherence and possible invasion. PEG 15-20 appeared to exert its protective effect via its binding to lipid rafts by preventing their coalescence, a hallmark feature in intestinal epithelial cells exposed to radiation.


Assuntos
Íleo/efeitos dos fármacos , Enteropatias/prevenção & controle , Mucosa Intestinal/efeitos dos fármacos , Microdomínios da Membrana/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Pseudomonas aeruginosa/efeitos dos fármacos , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/administração & dosagem , Sepse/prevenção & controle , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Aderência Bacteriana/efeitos dos fármacos , Linhagem Celular , Colesterol/metabolismo , Relação Dose-Resposta a Droga , Íleo/microbiologia , Íleo/patologia , Íleo/efeitos da radiação , Enteropatias/metabolismo , Enteropatias/patologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Masculino , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/microbiologia , Microdomínios da Membrana/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Pseudomonas aeruginosa/patogenicidade , Lesões Experimentais por Radiação/microbiologia , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Sprague-Dawley , Sepse/microbiologia , Fatores de Tempo , Virulência/efeitos dos fármacos
7.
Magn Reson Med ; 62(2): 348-56, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19449382

RESUMO

Imaging techniques are under development to facilitate early analysis of spatial patterns of tumor response to combined radiation and antivascular gene therapy. A genetically modified, replication defective adenoviral vector (Ad.EGR-TNFalpha), injected intratumorally, mediates infected cells to express tumor necrosis factor alpha (TNFalpha), which is increased after exposure to radiation. The goal of this study was to characterize an image based "signature" for response to this combined radiation and gene therapy in mice with human prostate xenografts. This study is part of an imaged guided therapy project where such a signature would be useful in guiding subsequent treatments. Changes in the tumor micro-environment were assessed using MRI registered with electron paramagnetic resonance imaging which provides images of tissue oxygenation. Dynamic contrast-enhanced MRI was used to assess tissue perfusion. When compared with null vector (control) treatment, the ratio of contrast agent (Gd-DTPA-BMA) washout rate to uptake rate was lower (P = 0.001) after treatment, suggesting a more balanced perfusion. Concomitantly, oxygenation significantly increased in the treated animals and decreased or did not change in the control animals (P < 0.025). This is the first report of minimally invasive, quantitative, absolute oxygen measurements correlated with tissue perfusion in vivo.


Assuntos
Terapia Genética/métodos , Imageamento por Ressonância Magnética/métodos , Imagem de Perfusão/métodos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Radioterapia Conformacional/métodos , Técnica de Subtração , Animais , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Humanos , Masculino , Camundongos , Camundongos Nus , Prognóstico , Resultado do Tratamento
8.
Cancer Res ; 67(19): 9214-20, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17909027

RESUMO

Elsewhere, we reported that multiple serial in vivo passage of a squamous cell carcinoma cells (SCC61) concurrent with ionizing radiation (IR) treatment resulted in the selection of radioresistant tumor (nu61) that overexpresses the signal transducer and activator of transcription 1 (Stat1)/IFN-dependent pathway. Here, we report that (a) the Stat1 pathway is induced by IR, (b) constitutive overexpression of Stat1 is linked with failure to transmit a cytotoxic signal by radiation or IFNs, (c) selection of parental cell line SCC61 against IFN-alpha and IFN-gamma leads to the same IR- and IFN-resistant phenotype as was obtained by IR selection, and (d) suppression of Stat1 by short hairpin RNA renders the IR-resistant nu61 cells radiosensitive to IR. We propose a model that transient induction of Stat1 by IFN, IR, or other stress signals activates cytotoxic genes and cytotoxic response. Constitutive overexpression of Stat1 on the other hand leads to the suppression of the cytotoxic response and induces prosurvival genes that, at high levels of Stat1, render the cells resistant to IR or other inducers of cell death.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Fator de Transcrição STAT1/metabolismo , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Resistencia a Medicamentos Antineoplásicos , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Humanos , Interferon-alfa/farmacologia , Interferon gama/farmacologia , Camundongos , Camundongos Nus , Transplante de Neoplasias , RNA Interferente Pequeno/genética , Tolerância a Radiação , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT1/biossíntese , Fator de Transcrição STAT1/genética , Transplante Heterólogo
9.
Nat Commun ; 10(1): 3959, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477729

RESUMO

Successful combinations of radiotherapy and immunotherapy depend on the presence of live T cells within the tumor; however, radiotherapy is believed to damage T cells. Here, based on longitudinal in vivo imaging and functional analysis, we report that a large proportion of T cells survive clinically relevant doses of radiation and show increased motility, and higher production of interferon gamma, compared with T cells from unirradiated tumors. Irradiated intratumoral T cells can mediate tumor control without newly-infiltrating T cells. Transcriptomic analysis suggests T cell reprogramming in the tumor microenvironment and similarities with tissue-resident memory T cells, which are more radio-resistant than circulating/lymphoid tissue T cells. TGFß is a key upstream regulator of T cell reprogramming and contributes to intratumoral Tcell radio-resistance. These findings have implications for the design of radio-immunotherapy trials in that local irradiation is not inherently immunosuppressive, and irradiation of multiple tumors might optimize systemic effects of radiotherapy.


Assuntos
Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Experimentais/terapia , Radioterapia/métodos , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Terapia Combinada , Perfilação da Expressão Gênica/métodos , Interferon gama/imunologia , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Tolerância a Radiação/genética
10.
Mol Cancer Ther ; 17(2): 407-418, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29030460

RESUMO

Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSB) can enhance radiation effects in the tumor and overcome therapeutic resistance without incurring off-target toxicities. Unrepaired DSBs can block cancer cell proliferation, promote cancer cell death, and induce cellular senescence. Given the slow progress to date translating novel DSB repair inhibitors as radiosensitizers, we have explored drug repurposing, a proven route to improving speed, costs, and success rates of drug development. In a prior screen where we tracked resolution of ionizing radiation-induced foci (IRIF) as a proxy for DSB repair, we had identified pitavastatin (Livalo), an HMG-CoA reductase inhibitor commonly used for lipid lowering, as a candidate radiosensitizer. Here, we report that pitavastatin and other lipophilic statins are potent inhibitors of DSB repair in breast and melanoma models both in vitro and in vivo When combined with ionizing radiation, pitavastatin increased persistent DSBs, induced senescence, and enhanced acute effects of radiation on radioresistant melanoma tumors. shRNA knockdown implicated HMG-CoA reductase, farnesyl diphosphate synthase, and protein farnesyl transferase in IRIF resolution, DSB repair, and senescence. These data confirm on-target activity of statins, although via inhibition of protein prenylation rather than cholesterol biosynthesis. In light of prior studies demonstrating enhanced efficacy of radiotherapy in patients taking statins, this work argues for clinical evaluation of lipophilic statins as nontoxic radiosensitizers to enhance the benefits of image-guided radiotherapy. Mol Cancer Ther; 17(2); 407-18. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."


Assuntos
Reparo do DNA/efeitos dos fármacos , Acil Coenzima A/farmacologia , Animais , Senescência Celular , Feminino , Humanos , Camundongos
11.
J Clin Invest ; 110(3): 403-10, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12163460

RESUMO

Ionizing radiation (IR) and radical oxygen intermediates (ROIs) activate the early growth response-1 (Egr1) promoter through specific cis-acting sequences termed CArG elements. Ad.Egr.TNF.11D, a replication-deficient adenoviral vector containing CArG elements cloned upstream of the cDNA for human recombinant TNF-alpha was used to treat human esophageal adenocarcinoma and rat colon adenocarcinoma cells in culture and as xenografts in athymic nude mice. Cisplatin, a commonly used chemotherapeutic agent, causes tumor cell death by producing DNA damage and generating ROIs. The present studies demonstrate induction of TNF-alpha production in tumor cells and xenografts treated with the combination of Ad.Egr.TNF.11D and cisplatin. The results show that the Egr1 promoter is induced by cisplatin and that this induction is mediated in part through the CArG elements. These studies also demonstrate an enhanced antitumor response without an increase in toxicity following treatment with Ad.Egr.TNF.11D and cisplatin, compared with either agent alone. Chemo-inducible cancer gene therapy thus provides a means to control transgene expression while enhancing the effectiveness of commonly used chemotherapeutic agents.


Assuntos
Cisplatino/farmacologia , Proteínas Imediatamente Precoces , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Adenocarcinoma/terapia , Adenoviridae/genética , Adenoviridae/fisiologia , Animais , Neoplasias do Colo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce , Neoplasias Esofágicas/terapia , Feminino , Terapia Genética , Vetores Genéticos/genética , Vetores Genéticos/fisiologia , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Regiões Promotoras Genéticas , Ratos , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/biossíntese
12.
Clin Exp Metastasis ; 24(7): 521-31, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17653822

RESUMO

TNFerade is a replication incompetent adenovector designed to express human TNFalpha under control of the Egr-1 radiation and chemotherapy enhanced promoter, and is currently in Phase II/III clinical testing. Data from Phase I clinical testing of TNFerade in a limited set of melanoma patients suggested the potential to impact distal metastases following intratumoral injections of TNFerade. These clinical observations and the multiple potential mechanisms of TNFerade led us to hypothesize local treatment with TNFerade + radiation may impact metastatic disease. We explored this hypothesis in preclinical models using the spontaneously metastatic, syngeneic B16F10 murine melanoma model. Established subcutaneous B16F10 tumors were treated with intratumoral injections of TNFerade and localized 2 Gy fractionated radiation therapy, modeling the clinical treatment regimen. Following 10-14 days of treatment, mice were evaluated for metastases development in the iliac and axillary lymph nodes. Comparisons of metastatic burden to control groups indicated TNFerade +/- radiation suppressed the formation of metastases in the lymph nodes. Additional experiments in TNF receptor knockout mice, where the only possible effects are on tumor cells containing the TNFalpha receptor, indicate TNFerade's local and distal activities are critically dependent on a host-mediated response. These data provide direct preclinical evidence local therapy of a solid tumor with TNFerade can also reduce metastatic disease, in addition to effects on the treated lesion. Furthermore, our finding of a host dependant response(s) for TNFerade at both the treated tumor and on lymph node metastases suggest the potential for broad activity independent of tumor histology.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética , Melanoma/terapia , Neoplasias/terapia , Fator de Necrose Tumoral alfa/genética , Adenoviridae/genética , Adulto , Animais , Terapia Combinada , Fracionamento da Dose de Radiação , Feminino , Seguimentos , Vetores Genéticos , Humanos , Metástase Linfática/prevenção & controle , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Transplante de Neoplasias , Receptores do Fator de Necrose Tumoral/genética , Células Tumorais Cultivadas
13.
Nat Commun ; 8(1): 1736, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-29170400

RESUMO

Radiotherapy induces and promotes innate and adaptive immunity in which host STING plays an important role. However, radioresistance in irradiated tumors can also develop, resulting in relapse. Here we report a mechanism by which extrinsic resistance develops after local ablative radiation that relies on the immunosuppressive action of STING. The STING/type I interferon pathway enhances suppressive inflammation in tumors by recruiting myeloid cells in part via the CCR2 pathway. Germ-line knockouts of CCR2 or treatment with an anti-CCR2 antibody results in blockade of radiation-induced MDSC infiltration. Treatment with anti-CCR2 antibody alleviates immunosuppression following activation of the STING pathway, enhancing the anti-tumor effects of STING agonists and radiotherapy. We propose that radiation-induced STING activation is immunosuppressive due to (monocytic) M-MDSC infiltration, which results in tumor radioresistance. Furthermore, the immunosuppressive effects of radiotherapy and STING agonists can be abrogated in humans by a translational strategy involving anti-CCR2 antibody treatment to improve radiotherapy.


Assuntos
Proteínas de Membrana/imunologia , Células Supressoras Mieloides/imunologia , Tolerância a Radiação/imunologia , Imunidade Adaptativa , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Neoplasias do Colo/radioterapia , Feminino , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR2/deficiência , Receptores CCR2/genética , Receptores CCR2/imunologia , Transdução de Sinais
14.
Cancer Res ; 63(2): 308-11, 2003 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-12543780

RESUMO

Ionizing radiation (IR) and concomitant angiostatin (AS) produce greater than additive local antitumor effects. We examined whether prolonged AS treatment added to IR reduces proliferation of lung metastases from LLC primary tumors. Flank tumors were treated with 40 Gy with or without AS (25 mg/kg/day). IR plus a 14-day course of AS improved local tumor control and blocked the increase in lung weights observed in the group receiving IR plus a 2-day course of AS group. Animals treated with prolonged AS exhibited no increase in lung weight and no macrometastases. These findings suggest that long-term treatment with antiangiogenic compounds may be effective in preventing metastases from IR-treated tumors as well as increasing the local antitumor effects of radiotherapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/radioterapia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Fragmentos de Peptídeos/farmacologia , Plasminogênio/farmacologia , Angiostatinas , Animais , Carcinoma Pulmonar de Lewis/secundário , Terapia Combinada , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Camundongos , Camundongos Endogâmicos C57BL
15.
Oncotarget ; 7(23): 33919-33, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27129153

RESUMO

Radiation therapy remains a significant therapeutic modality in the treatment of cancer. An attractive strategy would be to enhance the benefits of ionizing radiation (IR)with radiosensitizers. A high-content drug repurposing screen of approved and investigational agents, natural products and other small molecules has identified multiple candidates that blocked repair of IR damage in vitro. Here, we validated a subset of these hits in vitro and then examined effects on tumor growth after IR in a murine tumor model. Based on robust radiosensitization in vivo and other favorable properties of cephalexin, we conducted additional studies with other beta-lactam antibiotics. When combined with IR, each cephalosporin tested increased DNA damage and slowed tumor growth without affecting normal tissue toxicity. Our data implicate reactive oxygen species in the mechanism by which cephalosporins augment the effects of IR. This work provides a rationale for using commonly prescribed beta-lactam antibiotics as non-toxic radiosensitizers to enhance the therapeutic ratio of radiotherapy.


Assuntos
Antibacterianos/farmacologia , Neoplasias da Mama/radioterapia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Senescência Celular/efeitos dos fármacos , Senescência Celular/efeitos da radiação , Cefalosporinas/farmacologia , Reposicionamento de Medicamentos , Radiossensibilizantes/farmacologia , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cancer Chemother Pharmacol ; 56(3): 317-21, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15887016

RESUMO

We examined the interaction between forphenicinol (FPL) and cyclophosphamide (CPA) or ionizing radiation (IR) on the growth of murine squamous cell carcinoma tumors SCCVII. Primary tumors were established in C3H mice by injecting SCCVII tumor cells subcutaneously into the right hind limb. FPL (100 mg/kg for 8 days) and/or CPA (25 mg/kg twice) were administered by intraperitoneal injection. Tumors were irradiated to a total dose of 40 Gy (eight 5-Gy fractions). SCCVII tumor growth was inhibited by FPL (P=0.054), IR (P=0.003) and CPA (P<0.001) compared with control. The combination of FPL and CPA inhibited tumor growth additively compared with either treatment alone in both small- and large-volume tumors. FPL did not significantly enhance the antitumor effects of IR, however, when CPA+FPL were combined with IR, significant tumor growth inhibition was observed compared with FPL alone (P<0.001), CPA alone (P=0.002) and IR alone (P=0.002). Due to its low toxicity profile, FPL may be combined with CPA, IR and other cytotoxic therapies to potentially enhance the therapeutic ratio.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Ciclofosfamida/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Animais , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Sinergismo Farmacológico , Feminino , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C3H , Transplante de Neoplasias , Radioterapia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Mol Cancer Ther ; 3(9): 1167-75, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15367711

RESUMO

A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)6GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-alpha. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-alpha by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Terapia Genética , Neoplasias/terapia , Fator de Necrose Tumoral alfa/genética , Acetilcisteína/farmacologia , Adenoviridae/genética , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Terapia Combinada , Proteínas de Ligação a DNA/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Proteína 1 de Resposta de Crescimento Precoce , Terapia Genética/métodos , Vetores Genéticos , Humanos , Proteínas Imediatamente Precoces/genética , Masculino , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/terapia , Regiões Promotoras Genéticas/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Ratos , Fatores de Transcrição/genética , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
FEBS Lett ; 565(1-3): 167-70, 2004 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-15135073

RESUMO

We demonstrate that human umbilical vein endothelial cells (HUVEC) grown in co-culture (CC) with U87 glioblastoma cells transfected with green fluorescent protein (GFP-U87) exhibit resistance to radiation-mediated apoptosis. cDNA macroarray analysis reveals increases in the accumulation of RNAs for HUVEC genes encoding cell adhesion molecules, growth factor-related proteins, and cell cycle regulatory/DNA repair proteins. An increase in protein expression of integrin alphav, integrin beta1, MAPK(p42), Rad51, DNA-PK(CS), and ataxia telangiectasia gene (ATM) was detected in HUVEC grown in CC with GFP-U87 cells compared with HUVEC grown in mono-culture. Treatment with anti-VEGF antibody decreases the expression of integrin alphav, integrin beta1, DNA-PK(CS) and ATM with a corresponding increase in ionizing radiation (IR)-induced apoptosis. These data support the concept that endothelial cells growing in the tumor microenvironment may develop resistance to cytotoxic therapies due to the up-regulation by tumor cells of endothelial cells genes associated with survival.


Assuntos
Apoptose , Células Endoteliais/patologia , Glioblastoma/patologia , Proteínas Mutadas de Ataxia Telangiectasia , Western Blotting , Adesão Celular , Ciclo Celular , Proteínas de Ciclo Celular , Divisão Celular , Linhagem Celular Tumoral , Células Cultivadas , Técnicas de Cocultura , Reparo do DNA , DNA Complementar/metabolismo , Proteína Quinase Ativada por DNA , Proteínas de Ligação a DNA/metabolismo , Células Endoteliais/efeitos da radiação , Endotélio Vascular/citologia , Glioblastoma/radioterapia , Proteínas de Fluorescência Verde , Humanos , Raios Infravermelhos , Integrina alfaV/biossíntese , Integrina alfaVbeta3/metabolismo , Integrina beta1/biossíntese , Proteínas Luminescentes/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Nucleares , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/metabolismo , Rad51 Recombinase , Radioterapia , Recombinação Genética , Transcrição Gênica , Transfecção , Proteínas Supressoras de Tumor , Veias Umbilicais/citologia , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Int J Oncol ; 24(3): 731-6, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14767560

RESUMO

The promising benefits of cancer gene therapy have been limited by the inability to deliver therapeutic genes homogeneously throughout the tumor mass and to control gene expression within the tumor cells. Transcriptional targeting, the use of DNA regulatory promoter sequences to localize transgene expression, has been employed as a solution to circumvent these limitations. TNF-alpha is a cytokine that exhibits potent anticancer properties, but its utility following systemic administration is limited by toxicity. We review a strategy whereby ligating TNF-alpha to segments of the chemo-inducible EGR1 or MDR1 promoters activates expression of TNF-alpha cDNA and enhances effectiveness of gene therapy and chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Proteínas Imediatamente Precoces/genética , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Transcrição Gênica , Animais , Ensaios Clínicos como Assunto , Citotoxinas , DNA/metabolismo , Dano ao DNA , Proteína 1 de Resposta de Crescimento Precoce , Humanos , Modelos Biológicos , Radiação Ionizante , Fator de Necrose Tumoral alfa/metabolismo
20.
Cancer Chemother Pharmacol ; 50(5): 412-8, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12439600

RESUMO

PURPOSE: We examined the interaction between cyclophosphamide (CPA) and angiostatin (AS) on the growth of primary Lewis lung carcinoma (LLC) tumors and on the development of LLC pulmonary metastases. We studied the effects of AS and CPA on the stages of angiogenesis employing in vitro assays. METHODS: Primary tumor growth and pulmonary metastases were measured to evaluate the effects of treatment with AS alone, CPA alone or the combination of CPA and AS. We examined the effects of CPA plus AS on endothelial cell (HUVEC) survival, migration and tube formation. RESULTS: Combined treatment with CPA and AS did not significantly affect primary tumor growth when compared with CPA treatment alone. However, a significant decrease in the number of pulmonary metastases was observed following CPA plus AS treatment when compared with CPA treatment alone ( P<0.001). AS did not enhance CPA-mediated HUVEC cytotoxicity, and CPA failed to enhance AS-mediated inhibition of migration. However, tube formation was inhibited following combined treatment with CPA and AS when compared with either treatment alone. CONCLUSIONS: AS enhanced the antimetastatic effects of CPA without significantly influencing the effects of CPA on primary tumor growth. CPA plus AS inhibited tube formation, suggesting that interrupting specific steps in the angiogenesis process might be an effective approach to the treatment of subclinical distant metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/análogos & derivados , Ciclofosfamida/farmacologia , Metástase Neoplásica/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Plasminogênio/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Angiostatinas , Animais , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/secundário , Movimento Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Modelos Lineares , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos C57BL , Morfogênese/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Plasminogênio/administração & dosagem , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/farmacologia , Método Simples-Cego , Células Tumorais Cultivadas/transplante
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