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1.
Cancer Sci ; 109(12): 3993-4002, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30447042

RESUMO

Angiogenesis inhibitors such as lenvatinib and sorafenib, and an immune checkpoint inhibitor (ICI), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma (HCC). Combination treatments comprising angiogenesis inhibitors plus ICIs are promising options for improving clinical benefits in HCC patients, and clinical trials are ongoing. Here, we investigated the antitumor and immunomodulatory activities of lenvatinib (a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor α, KIT and RET) and the combined antitumor activity of lenvatinib plus anti-programmed cell death 1 (PD-1) antibody in the Hepa1-6 mouse HCC syngeneic model. We found that the antitumor activities of lenvatinib and sorafenib were not different in immunodeficient mice, but lenvatinib showed more potent antitumor activity than sorafenib in immunocompetent mice. The antitumor activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+ T cell depletion. Treatment with lenvatinib plus anti-PD-1 antibody resulted in more tumor regression and a higher response rate compared with either treatment alone in immunocompetent mice. Single-cell RNA sequencing analysis demonstrated that treatment with lenvatinib with or without anti-PD-1 antibody decreased the proportion of monocytes and macrophages population and increased that of CD8+ T cell populations. These data suggest that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti-PD-1 antibody. Combination treatment of lenvatinib plus anti-PD-1 antibody therefore warrants further investigation against advanced HCC.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Sorafenibe/administração & dosagem , Animais , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Imunocompetência , Imunomodulação , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Camundongos , Compostos de Fenilureia/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Quinolinas/farmacologia , Análise de Sequência de RNA , Análise de Célula Única , Sorafenibe/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cancer Sci ; 108(4): 763-771, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28107584

RESUMO

The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, plus everolimus, a mammalian target of rapamycin (mTOR) inhibitor, significantly improved clinical outcomes versus everolimus monotherapy in a phase II clinical study of metastatic renal cell carcinoma (RCC). We investigated potential mechanisms underlying the antitumor activity of the combination treatment in preclinical RCC models. Lenvatinib plus everolimus showed greater antitumor activity than either monotherapy in three human RCC xenograft mouse models (A-498, Caki-1, and Caki-2). In particular, the combination led to tumor regression in the A-498 and Caki-1 models. In the A-498 model, everolimus showed antiproliferative activity, whereas lenvatinib showed anti-angiogenic effects. The anti-angiogenic activity was potentiated by the lenvatinib plus everolimus combination in Caki-1 xenografts, in which fibroblast growth factor (FGF)-driven angiogenesis may contribute to tumor growth. The combination showed mostly additive activity in vascular endothelial growth factor (VEGF)-activated, and synergistic activity against FGF-activated endothelial cells, in cell proliferation and tube formation assays, as well as strongly suppressed mTOR-S6K-S6 signaling. Enhanced antitumor activities of the combination versus each monotherapy were also observed in mice bearing human pancreatic KP-1 xenografts overexpressing VEGF or FGF. Our results indicated that simultaneous targeting of tumor cell growth and angiogenesis by lenvatinib plus everolimus resulted in enhanced antitumor activity. The enhanced inhibition of both VEGF and FGF signaling pathways by the combination underlies its superior anti-angiogenic activity in human RCC xenograft models.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neovascularização Patológica/prevenção & controle , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Western Blotting , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Sinergismo Farmacológico , Everolimo/administração & dosagem , Everolimo/farmacologia , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Cancer Sci ; 105(10): 1334-42, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25060424

RESUMO

Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor of microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show that eribulin induces remodeling of tumor vasculature through a novel antivascular activity in MX-1 and MDA-MB-231 human breast cancer xenograft models. Vascular remodeling associated with improved perfusion was shown by Hoechst 33342 staining and by increased microvessel density together with decreased mean vascular areas and fewer branched vessels in tumor tissues, as determined by immunohistochemical staining for endothelial marker CD31. Quantitative RT-PCR analysis of normal host cells in the stroma of xenograft tumors showed that eribulin altered the expression of mouse (host) genes in angiogenesis signaling pathways controlling endothelial cell-pericyte interactions, and in the epithelial-mesenchymal transition pathway in the context of the tumor microenvironment. Eribulin also decreased hypoxia-associated protein expression of mouse (host) vascular endothelial growth factor by ELISA and human CA9 by immunohistochemical analysis. Prior treatment with eribulin enhanced the anti-tumor activity of capecitabine in the MDA-MB-231 xenograft model. These findings suggest that eribulin-induced remodeling of abnormal tumor vasculature leads to a more functional microenvironment that may reduce the aggressiveness of tumors due to elimination of inner tumor hypoxia. Because abnormal tumor microenvironments enhance both drug resistance and metastasis, the apparent ability of eribulin to reverse these aggressive characteristics may contribute to its clinical benefits.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Furanos/farmacologia , Cetonas/farmacologia , Moduladores de Tubulina/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Neoplasias da Mama/patologia , Capecitabina , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Feminino , Fluoruracila/análogos & derivados , Fluoruracila/farmacologia , Humanos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Bioorg Med Chem ; 22(19): 5513-29, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25139751

RESUMO

Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560 nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47 nM, respectively), and in vivo. Additionally, 43a (12.5-100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.


Assuntos
Anilidas/química , Anilidas/farmacologia , Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Anilidas/administração & dosagem , Anilidas/síntese química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade
5.
Cancer Res Commun ; 4(7): 1881-1893, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38984877

RESUMO

Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms. SIGNIFICANCE: A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.


Assuntos
Anticorpos Neutralizantes , Neovascularização Patológica , Receptor Notch4 , Animais , Receptor Notch4/metabolismo , Camundongos , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Neovascularização Patológica/metabolismo , Feminino , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo
6.
Mol Cancer Ther ; 22(4): 499-510, 2023 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-36696578

RESUMO

Eribulin is a microtubule dynamics inhibitor with tumor microenvironment modulation activity such as vascular remodeling activity. Here, we investigated antitumor and immunomodulatory activities of eribulin and its liposomal formulation (eribulin-LF) as monotherapies or in combination with anti-programmed death 1 (PD-1) Ab. The antitumor activity of eribulin or eribulin-LF as monotherapy or in combination with anti-PD-1 Ab was examined in a P-glycoprotein-knockout 4T1 model. Eribulin and eribulin-LF showed stronger antitumor activity in immunocompetent mice compared with immunodeficient mice, indicating that they have immunomodulatory activity that underlies its antitumor activity. Combination therapy of eribulin and eribulin-LF with anti-PD-1 Ab showed antitumor activity, and the combination activity of eribulin-LF with anti-PD-1 Ab was observed at a lower dose and longer interval of administration compared with that using eribulin. To examine the immunomodulatory activity of eribulin and eribulin-LF and its underlying mechanisms, we performed flow cytometry, IHC, and gene expression profiling. IHC and flow cytometry revealed that eribulin-LF increased microvessel density and intratumoral populations of cytotoxic T cells and natural killer cells rather than eribulin. Gene expression profiling demonstrated that eribulin-LF induces IFNγ signaling. Furthermore, IHC also showed that eribulin-LF increased infiltration of CD8-positive cells together with increased CD31-positive cells. Eribulin-LF also increased ICAM-1 expression, which is essential for lymphocyte adhesion to vascular endothelial cells. In conclusion, eribulin showed combination antitumor activity with anti-PD-1 Ab via immunomodulation due to its vascular remodeling activity, and the liposomal formulation showed improved antitumor activity over the standard formulation.


Assuntos
Lipossomos , Remodelação Vascular , Animais , Camundongos , Células Endoteliais , Linhagem Celular Tumoral
7.
Cancer Res ; 82(2): 292-306, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34753772

RESUMO

Combination therapies consisting of immune checkpoint inhibitors plus anti-VEGF therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of FGF/FGFR signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGFR and FGFR. Here, we examine the antitumor activity of anti-PD-1 mAb combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of IFNγ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb. SIGNIFICANCE: FGFR pathway activation inhibits IFNγ signaling in tumor cells, and FGFR inhibition with lenvatinib enhances antitumor immunity and the activity of anti-PD-1 antibodies.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Interferon gama/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Compostos de Fenilureia/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Quinolinas/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Renais/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/imunologia , Resultado do Tratamento
8.
Cancer Res ; 81(4): 1052-1062, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33408116

RESUMO

The Wnt/ß-catenin signaling pathway plays crucial roles in embryonic development and the development of multiple types of cancer, and its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor of the interaction between ß-catenin and CREB binding protein, which is part of the Wnt/ß-catenin signaling pathway, disrupts the Wnt/ß-catenin signaling pathway in HEK293 and adenomatous polyposis coli (APC)-mutated human gastric cancer ECC10 cells. It also inhibited tumor growth in an ECC10 xenograft model and suppressed polyp formation in the intestinal tract of ApcMin /+ mice, in which mutation of Apc activates the Wnt/ß-catenin signaling pathway. E7386 demonstrated antitumor activity against mouse mammary tumors developed in mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice. Gene expression profiling using RNA sequencing data of MMTV-Wnt1 tumor tissue from mice treated with E7386 showed that E7386 downregulated genes in the hypoxia signaling pathway and immune responses related to the CCL2, and IHC analysis showed that E7386 induced infiltration of CD8+ cells into tumor tissues. Furthermore, E7386 showed synergistic antitumor activity against MMTV-Wnt1 tumor in combination with anti-PD-1 antibody. In conclusion, E7386 demonstrates clear antitumor activity via modulation of the Wnt/ß-catenin signaling pathway and alteration of the tumor and immune microenvironments, and its antitumor activity can be enhanced in combination with anti-PD-1 antibody. SIGNIFICANCE: These findings demonstrate that the novel anticancer agent, E7386, modulates Wnt/ß-catenin signaling, altering the tumor immune microenvironment and exhibiting synergistic antitumor activity in combination with anti-PD-1 antibody.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/patologia , Fragmentos de Peptídeos/metabolismo , Pirazinas/farmacologia , Sialoglicoproteínas/metabolismo , Triazinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Genes APC , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Pirazinas/uso terapêutico , Sialoglicoproteínas/antagonistas & inibidores , Triazinas/uso terapêutico , Via de Sinalização Wnt/genética , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , beta Catenina/antagonistas & inibidores
9.
PLoS One ; 14(2): e0212513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30811474

RESUMO

Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. We investigated the immunomodulatory activities of lenvatinib in the tumor microenvironment and its mechanisms of enhanced antitumor activity when combined with a programmed cell death-1 (PD-1) blockade. Antitumor activity was examined in immunodeficient and immunocompetent mouse tumor models. Single-cell analysis, flow cytometric analysis, and immunohistochemistry were used to analyze immune cell populations and their activation. Gene co-expression network analysis and pathway analysis using RNA sequencing data were used to identify lenvatinib-driven combined activity with anti-PD-1 antibody (anti-PD-1). Lenvatinib showed potent antitumor activity in the immunocompetent tumor microenvironment compared with the immunodeficient tumor microenvironment. Antitumor activity of lenvatinib plus anti-PD-1 was greater than that of either single treatment. Flow cytometric analysis revealed that lenvatinib reduced tumor-associated macrophages (TAMs) and increased the percentage of activated CD8+ T cells secreting interferon (IFN)-γ+ and granzyme B (GzmB). Combination treatment further increased the percentage of T cells, especially CD8+ T cells, among CD45+ cells and increased IFN-γ+ and GzmB+ CD8+ T cells. Transcriptome analyses of tumors resected from treated mice showed that genes specifically regulated by the combination were significantly enriched for type-I IFN signaling. Pretreatment with lenvatinib followed by anti-PD-1 treatment induced significant antitumor activity compared with anti-PD-1 treatment alone. Our findings show that lenvatinib modulates cancer immunity in the tumor microenvironment by reducing TAMs and, when combined with PD-1 blockade, shows enhanced antitumor activity via the IFN signaling pathway. These findings provide a scientific rationale for combination therapy of lenvatinib with PD-1 blockade to improve cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Compostos de Fenilureia/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Quinolinas/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Fatores Imunológicos/administração & dosagem , Interferons/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Neoplasias Experimentais/genética , Inibidores de Proteínas Quinases/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
10.
Anticancer Res ; 37(12): 6629-6638, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29187438

RESUMO

BACKGROUND/AIM: Tumor angiogenesis induced by vascular endothelial growth factor (VEGF) and/or fibroblast growth factor (FGF) plays an important role in tumor growth, metastasis, and drug resistance. However, the characteristics of tumor vessels derived from these angiogenic factors have not been fully explored. MATERIALS AND METHODS: To functionally examine tumor vessels, we developed in vivo VEGF- and FGF-induced tumor blood vessel models. We performed immunohistochemistry and Hoechst perfusion assay to elucidate histopathological differences between the derived tumor vessels. To kinetically understand tumor perfusion, we employed radiolabeled PEGylated liposomes. RESULTS: While tumor vessel density was substantially increased by enhanced expression levels of VEGF and FGF, permeability of VEGF-driven tumor vessels was significantly higher than that of FGF-driven ones, the latter demonstrating an increased number of pericyte-covered vessels. Accordingly, we observed an increased tumor retention of the PEGylated liposomes in the VEGF-driven tumor. CONCLUSION: Our in vivo models of tumor vessel demonstrate the frequency of pericyte coverage and tumor perfusion levels as major functional differences between VEGF- and FGF-driven tumor vessels.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias/irrigação sanguínea , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Fatores de Crescimento de Fibroblastos/genética , Humanos , Imuno-Histoquímica , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neovascularização Patológica/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/farmacologia , Sorafenibe , Fator A de Crescimento do Endotélio Vascular/genética , Gencitabina
11.
Cancer Res ; 62(21): 6116-23, 2002 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-12414636

RESUMO

In the process of angiogenesis, endothelial adhesion molecules play a significant role in vascular morphogenesis, in coordination with angiogenic factor signaling. Here we report that a novel angiogenesis inhibitor, E7820 (an aromatic sulfonamide derivative), inhibited in vitro proliferation and tube formation of human umbilical vascular endothelial cell (HUVEC). E7820 decreased integrin alpha2, 3, 5, and beta1 in confluent culture of HUVEC, and integrin alpha2 was initially suppressed in mRNA level, followed by decrement of integrins alpha3, 5, and beta1. The inhibition of integrin alpha2 expression in HUVEC showed dose dependence but did not alter the level of CD31. Up-regulation of integrin alpha2 by phorbol 12-myristate 13-acetate abrogated the inhibitory effect of E7820 on tube formation within type I collagen gel, whereas addition of antibody against integrin alpha2 canceled the phorbol 12-myristate 13-acetate effect. These results suggest that E7820 inhibited tube formation through the suppression of integrin alpha2. Oral administration of E7820 remarkably resulted in inhibition of tumor-induced angiogenesis in mouse dorsal air sac model, and tumor growth of human colorectal tumor cell lines (WiDr and LoVo) was inhibited in xenotransplanted model in mice. This is the first time that a small molecule has been shown to modulate integrins, and this finding may provide the basis for a new approach to antiangiogenic therapy through the suppression of integrin alpha2 on endothelium.


Assuntos
Inibidores da Angiogênese/farmacologia , Endotélio Vascular/efeitos dos fármacos , Indóis/farmacologia , Integrina alfa2/biossíntese , Sulfonamidas/farmacologia , Animais , Divisão Celular/efeitos dos fármacos , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/tratamento farmacológico , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Chemother Pharmacol ; 69(5): 1353-62, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22349812

RESUMO

PURPOSE: Indisulam (N-(-3-chloro-7-indolyl)-1,4-benzenedisulfonamide; E7070) is an experimental anticancer agent. Microarray analysis indicates that indisulam downregulates several genes involved in drug resistance, and this finding led us to test the effect of combining indisulam with other anticancer drugs. We investigated the antitumor effect and mechanism of synergism when indisulam was administered in combination with CPT-11. METHODS: In vitro cytotoxic activity was examined using a cell counter kit, and the combination effect was determined by isobologram analysis. The level of topoisomerase IIα was measured by Western blotting. The in vivo antitumor effect was assessed in mice inoculated with human colorectal cancer SW620 cells. RESULTS: Isobologram analysis indicated that a 24-h exposure to indisulam and SN-38, an active metabolite of CPT-11, had a synergistic effect in HCT116 and SW620 cells and an additive effect in HCT15 and WiDr cells. Prolongation of exposure to 48 h resulted in a synergistic effect in HCT15 and WiDr cells. Treatment with SN-38 alone increased the amount of intracellular topoisomerase IIα in all cell lines tested. Co-treatment with indisulam suppressed the SN-38-induced upregulation of topoisomerase IIα after 24 h of exposure in HCT116 and SW620 cells and after 48 h of exposure in HCT15 and WiDr cells. This apparent association between a synergistic effect and suppression of SN-38-mediated upregulation of topoisomerase IIα suggests that indisulam enhances SN-38 cytotoxicity by suppressing topoisomerase IIα upregulation to compensate for topoisomerase I inhibition by SN-38. Synergy was also observed in xenografted tumors and was accompanied by complete suppression of topoisomerase IIα upregulation induced by CPT-11 treatment. CONCLUSION: These observations prompted the clinical evaluation of indisulam and CPT-11 combination therapy.


Assuntos
Antígenos de Neoplasias/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , DNA Topoisomerases Tipo II/efeitos dos fármacos , Proteínas de Ligação a DNA/efeitos dos fármacos , Animais , Antígenos de Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Western Blotting , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , DNA Topoisomerases Tipo I/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Irinotecano , Camundongos , Camundongos Nus , Análise em Microsséries , Sulfonamidas/administração & dosagem , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Mol Med ; 29(4): 541-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22211243

RESUMO

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that play crucial roles in the adaptation of cancer cells to hypoxia. HIF-1α overexpression has been associated with poor prognosis in patients with various types of cancer. Here, we describe ER-400583-00 as a novel HIF-1 inhibitor. ER-400583-00 suppressed the production of HIF-1α protein in response to hypoxia, with a half-maximal inhibitory concentration value of 3.7 nM in human U251 glioma cells. The oral administration of 100 mg/kg ER-400583-00 to mice bearing U251 tumor xenografts resulted in a rapid suppression of HIF-1α that persisted for 24 h. Immunohistochemical analysis revealed that ER-400583-00 suppressed the proliferation of cancer cells most prominently in areas distal to the region of blood perfusion, where HIF-1α-expressing hypoxic cancer cells were located. These hypoxic cancer cells were resistant to radiation therapy. ER-400583-00 showed a synergistic interaction with radiation therapy in terms of antitumor activity. These data suggest that HIF-1 blockade by small compounds may have therapeutic value in cancer, especially in combination with radiation therapy.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Glioma/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Piperazinas/farmacologia , Administração Oral , Animais , Antineoplásicos/uso terapêutico , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Glioma/radioterapia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Bioorg Med Chem Lett ; 12(16): 2097-100, 2002 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-12127512

RESUMO

We herein report the synthesis and antitumor activity of E7070 analogues containing a 3-pyridinesulfonamide moiety. E7070 was selected from our sulfonamide-based compound collections, currently undergoing Phase II clinical trials because of its tolerable toxicity profile and some antitumor responses in the Phase I setting. Of the analogues examined, ER-35745, a 6-amino-3-pyridinesulfonamide derivative, demonstrated significant oral efficacy against the HCT116 human colon carcinoma xenograft in nude mice.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Células Tumorais Cultivadas
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