All the results showed that TCMs can provide a source for discovering anti-angiogenic agents for the treatment of cancer, and all these experiments in the zebrafish and mammalian models further confirmed the value of zebrafish model in anti-angiogenic drug discovery. / Angiogenesis refers to the formation of new blood capillaries from pre-existing ones, and is essential in a series of normal physiological processes such as embryonic development and pathological responses. However, persistent unregulated angiogenesis causes "angiogenic diseases" such as diabetic retinopathy, tumor growth and metastasis, rheumatoid arthritis, and inflammatory diseases. The linkage between angiogenesis, tumor growth and metastasis was first hypothesized by Dr. Judah Folkman in the 1970s, and now this controversial idea is widely accepted and the inhibition of angiogenesis, or anti-angiogenesis, is considered as a promising anticancer therapeutic strategy. Bevacizumab (Avastin RTM by Genentech Inc.), the first approved anti-angiogenic drug by U.S. FDA in 2004, is a humanized monoclonal antibody to inhibit endothelial cell proliferation and angiogenesis for the treatment of metastatic colorectal cancer, non-small cell lung cancer, advanced breast cancer, glioblastoma, metastatic renal cell cancer. / Anti-angiogenic therapy in cancer treatment has led to the development of compounds designed to control a tumor's growth by blocking its ability to develop a blood supply. The development of agents with different mechanisms of action requires powerful preclinical models for the analysis and optimization of the therapy. Some in vitro and in vivo anti-angiogenic assays are already developed, for example, Human Umbilical Vein Endothelial Cell (HUVEC) assay, Chorioallantoic Membrane assay, Matrigel plug assay et al. Zebrafish, as a relatively new model organism, is firmly established as a powerful research platform for many areas of biology and drug discovery, allowing the testing of bioactive compounds in a whole organism and in cells undergoing normal cell-cell and cell-matrix interactions. Many anti- and pro-angiogenic molecules tested in zebrafish demonstrated similar effects to those observed in humans or other mammalian models. Besides providing a powerful platform for drug screening, zebrafish model can also be used for probing biological processes, and generate insights into mechanisms. / Cancer is a generic term for a large group of diseases that can affect any part of the body, which causes a vast medical problem and is a leading cause of death worldwide nowadays. However, for many years the main methods of treating cancer have been surgery, radiotherapy and chemotherapy. Among these treatments, chemotherapy has played a major role in cancer therapy for half a century. Despite improving managements and efforts, it is not surprising that the prognosis has not greatly improved because of the limitations of current therapies, such as toxicity, inherent and acquired resistance, and metastatic spread. This calls for novel cancer therapies and new group of anticancer agents for selectively targeting cancers without or with lower toxicity to normal tissues. / Traditional Chinese medicines (TCMs) have long been recognized as a rich source for discovering drugs, and various TCMs and their components have shown anti-angiogenic properties. In this thesis study, as a continuing pursuit for elucidating the anti-angiogenic properties of TCMs, our attention is focused on those with effects of anti-inflammation, anti-rheumatoid arthritis and anti-cancer. On zebrafish screening model, three of the selected TCMs, Rheum palmatum, Alpinia oxyphylla (seeds), and Kaempferia galanga showed potential anti-angiogenic activity, indicating the existence of potent anti-angiogenic components in these herbs. The ethyl acetate fraction of R. palmatum showed strong inhibition of vessel formation in zebrafish embryos. Further testing of the anthraquinones of this herb showed three of them displayed potent anti-angiogenic activities. The most potent compound---rhein could inhibit HUVEC migration and affect the mRNA expression of vegfa, kdr, angiopoietin1/2 and tie1/2; The n-hexane and ethyl acetate fractions of A. oxyphylla and K. galangal showed anti-angiogenic potentials both in zebrafish and HUVEC assays. The n-hexane and ethyl acetate fractions of A. oxyphylla could both inhibit the proliferation, migration and tube formation processes of HUVEC. And the most potential component, trans-ethyl-p-methoxycinnamate from K. galanga, could inhibit HUVEC migration and tube formation, and reduce all gene expressions involved in angiogenesis process except for vegfa. / He, Zhiheng. / Adviser: Wei Ge. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 87-108). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

The rapid discovery of novel therapeutic agents, targeting the specific mechanism of cancer progression, invasion and angiogenesis, necessitates the development and validation of efficient techniques to assess the therapeutic efficacy of these drugs in vivo. Recently the development of dedicated PET scanners for the imaging of small animals, such as the microPET system (CTI Concorde R4), has allowed for the high-resolution functional and molecular imaging of murine and rodent models of disease. This study, investigates the ability of microPET imaging, using the 18F labelled 2-fluoro-2-deoxyglucose (FDG) PET tracer, to detect the therapeutic efficacy of novel targeted therapies in a rat model of glioma. This technique potentially allows for the rapid and high-throughput assessment of tumour response and evaluation of efficacy of such therapeutic agents in vivo at the pre-clinical stage and will, consequently, facilitate the translation of these novel drugs from the discovery to the clinical phases. / La découverte accélérée de nouvelles molécules thérapeutiques qui ciblent lesmécanismes de progression du cancer tels que l'invasion et l'angiogenèse, nécessite lamise au point et la validation de techniques efficaces qui permettent d'évaluer l'efficacitéthérapeutique de ces agents in vivo. Le développement récent des scanners detomographie à émission de positron (TEP) dédiés à l'imagerie de petits animaux(microPET, CT! Concorde R4), permet aujourd'hui d'obtenir une image fonctionnelle etmoléculaire de haute résolution des modèles rongeurs. Cette étude s'intéresse au potentieldu 18F-2-fluoro-2-deoxyglucose (FDG) en utilisant l'imagerie microPET dansl'évaluation de l'efficacité de nouveaux agents thérapeutiques dans un modèle de gliomechez le. rat. Cette technique pourrait éventuellement mener à une évaluation rapide et àgrande échelle de la réponse tumorale, ainsi que la mesure de l'efficacité d'agentsthérapeutiques in vivo au stade d'étude préclinique. Globalement, cette étude a pour butde faciliter la transition entre la découverte de nouvelles molécules thérapeutiques et leursapplications cliniques.

No description available.

Objetivo: Comparar o efeito da terapia da fotocoagulação panretiniana (PFC) associada à injeção intravítrea de Ranibizumabe (RBZ) versus terapia isolada com PFC em pacientes com retinopatia diabética proliferativa (RDP) precoce, virgens de tratamento, com ou sem edema macular diabético (DME) durante 6 meses de acompanhamento. Projeto: Estudo prospectivo intervencionista, randomizado e controlado. Métodos: Sessenta olhos de 30 pacientes com RDP bilateral precoce foram randomizados para o grupo de estudo (GE) que foram tratados com PFC associado a duas injeções de RBZ intravítreo (0.5mg/0.05ml) ou para o grupo controle (GC) tratados apenas com PFC. Mudanças na acuidade visual (AV) corrigida, na sensibilidade ao contraste (SC) e na espessura foveal (EF) foram comparados no início, e nos 1, 3 e 6 meses após o tratamento. Resultados: No GE, a diferença na média da AV do baseline para o mês 6 teve um aumento significativo de + 3,4 letras (p = 0,006) e uma diminuição significativa na EF de - 47.6um (p < 0,001). No GC, a diferença na média da AV teve uma diminuição de - 3,4 letras (p = 0,04) e uma mudança na EF de -3.8 um (p = 0,96). Com relação ao teste de SC dentre os 28 olhos do GE, houve uma melhora no mês 6 em relação ao baseline nos ciclos: 1,5 (p < 0.001) e 3,0 ciclo (p=0.023). Dentre os 30 olhos do GC, não houve uma diferença estatística nos momentos estudados. Conclusão: A injeção intravítrea de RBZ associado com PFC pode ser um tratamento eficaz em olhos de pacientes com RDP precoce e EMD / Purpose: To compare the efficacy of therapy with panretinal photocoagulation (PRP) and intravitreal ranibizumab (RBZ) injection versus PRP alone in patients with treatment-naive bilateral non-high risk proliferative diabetic retinopathy (PDR) with and without diabetic macular edema (DME) with a 6-month follow-up. Design: Prospective, interventional, randomized controlled trial. Methods: Sixty eyes of 30 patients with bilateral non-high risk PDR were randomized either to the study group (SG) receiving PRP plus two intravitreal ranibizumab injections (0.5mg/0.05ml), the first one week before and the second four weeks after the PRP or to the control group (CG) receiving PRP alone. Mean change in best-corrected visual acuity (BCVA), contrast sensitivity (CS) and central macular thickness (CMT) were compared at baseline and 1, 3 and 6 months after treatment. Results: Changes from baseline to 6 months showed in the SG an increased in the BCVA by + 3.4 letters (p= 0.006) with a decrease in CMT by - 47.6um (p < 0.001). In the CG, a decrease by - 3.4 letters (p = 0.04) and an decrease by -3.8um (p= 0.96). Regarding the CS in the SG, there was an improvement compared to baseline for the sixth month in the 1.5 (p < 0.001) and 3.0 cycles (p = 0.023). The CG did not show significant results from baseline to month 6. Conclusion: Intravitreal RBZ associated with PRP can be an effective treatment in eyes with non-high risk PDR and DME

INTRODUÇÃO: O presente estudo avaliou o tratamento com injeções intravítreas de Bevacizumabe (IVB) associadas à panfotocoagulação (PFC) da retina na retinopatia diabética proliferativa (RDP) de alto risco com ou sem edema macular (EM). MÉTODOS: Ensaio clínico randomizado, prospectivo, aberto e mascarado composto por pacientes com Diabetes melitos (DM) tipo 2. A acuidade visual (AV) foi medida com a tabela Early Treatment Diabetic Retinopathy Study e a sensibilidade ao contraste (SC) pela da tabela Vistech Consultants Incorporation 6500. Os pacientes foram submetidos a exame de angiofluoresceinografia para observação de neovascularização retiniana e isquemia macular e à tomografia de coerência óptica (OCT), para se obter a espessura foveal (EF) e o volume macular (VM). Após os exames, um dos olhos do mesmo paciente foi randomizado para realizar somente PFC, grupo controle (GC), e o outro para PFC associado a injeções IVB, grupo de estudo (GE). A hemorragia vítrea (HV) e a presença de complicações também foram avaliadas. RESULTADOS: Dos 42 pacientes incluídos, 35 completaram o estudo. A média de idade foi de 56±8 anos, com predominância do gênero masculino 21 (60%). Vinte e seis (74%) pacientes eram portadores de Hipertensão Arterial Sistêmica com média de duração de 9±10 anos. A média de duração do DM foi de 18±9 anos sendo 23 (66%) usuários de insulina e 21 (68,5%), fácicos. A AV e a SC não demonstraram diferença entre os grupos no total da amostra. O GE demonstrou melhora em comparação ao GC na EF no 1º mês, e no VM nos 1° e 3º meses de seguimento. Quanto aos 12 pacientes com EM bilateral somente a EF demonstrou redução no GE no 1º mês de seguimento. Ao se avaliar os grupos separadamente, o GC apresentou agravamento da AV e SC durante todo seguimento. Houve também aumento da EF nos 1º e 6º meses e VM nos 1º , 3º e 6º meses de seguimento. O GE demonstrou estabilização da AV, SC, EF e VM. Correlacionado às funções visuais, AV com a SC, toda vez que houve piora da AV esta foi acompanhada pelo agravamento da SC em todos os momentos no GC e GE. Quando correlacionadas as AV e SC com as EF e VM, toda vez que a espessura macular aumentava, havia piora da função visual. Dos sete pacientes excluídos do estudo por apresentarem HV, cinco integravam o GC e dois o GE. Não houve aparecimento de catarata, endoftalmite e/ou aumento significativo da pressão ocular. CONCLUSÃO: Na RDP de alto risco, o uso adjuvante de injeções intravítreas de Bevacizumabe associadas à panfotocoagulação da retina pode estabilizar a AV, SC, EF e VM, diminuir a incidência de HV e reduzir a da espessura macular. Em relação à correlação entre as variáveis, quando houve piora da AV, esta foi acompanhada da piora da SC e o aumento da EF e VM causaram piora da AV e SC / INTRODUCTION: This study evaluated the treatment with intravitreal injections of Bevacizumab (IVB) associated with panretinal photocoagulation (PRP) in high-risk proliferative diabetic retinopathy (PDR) with or without diabetic macular edema (DME). METHODS: Prospective, open and masked, randomized clinical trial, composed of patients with type 2 Diabetes Mellitus (DM). The visual acuity (VA) was measured with the Early Treatment Diabetic Retinopathy Study charts and the contrast sensitivity (CS) through the chart of Vistech Consultants Incorporation 6500. Patients were submitted to a fluorescein angiography examination to observe retinal neovascularization and macular ischemia and to an optical coherence tomography (OCT) to obtain the foveal thickness (FT) and macular volume (MV). After the tests, one of the eyes from the same patient was randomized to realize only the PRP, the control group (CG), and the other for PRP associated to IVB injections, the study group (SG). Vitreous hemorrhage (VH) and presence of complications were also evaluated. RESULTS: Thirty-five of the forty-two patients included, completed the study. The mean age was 56±8 years, with a predominance of 21 (60%) males. Twenty-six (74%) patients had systemic hypertension with a mean duration of 9±10 years. The mean duration of DM was 18±9 years, of which 23 (66%) were insulin users and 21 (68.5%) were phakic. The VA and CS showed no difference between groups in the total sample. The SG showed improvement compared to the CG in FT for the 1st month, and in MV for the 1st and 3rd month of follow-up. As for the 12 patients with bilateral ME, only the FT showed a reduction in the SG for the 1st month of follow-up. When evaluating the groups separately, the CG showed worsening of VA and CS at all times. There was also an increase of FT for the 1st and 6th months and of MV for the 1st, 3rd and 6th month follow-up. The SG showed stabilization of VA, CS, FT and MV. When correlated to visual functions, VA and CS, a worsening of the VA was accompanied every time by a worsening of the CS in both the CG and SG. When VA and CS are correlated to FT and MV, there was worsening of visual function whenever macular thickness increased. Of the seven patients excluded from the study by presenting VH, 5 belonged to the CG and the 2 to the SG. There was no incidence of cataracts, endophthalmitis and/or significant increase in intraocular pressure. CONCLUSION: In high-risk PDR, intraocular injections of Bevacizumab as an adjuvant treatment to PRP, can stabilize VA, CS, FT and MV, reduce of the incidence of VH and decrease the macular thickness. Regarding the correlation between variables, when there was a worsening of VA, this was accompanied by a worsening of the CS, and an increase in FT and MV caused the worsening of the VA and CS

Objetivo: Comparar o efeito da terapia da fotocoagulação panretiniana (PFC) associada à injeção intravítrea de Ranibizumabe (RBZ) versus terapia isolada com PFC em pacientes com retinopatia diabética proliferativa (RDP) precoce, virgens de tratamento, com ou sem edema macular diabético (DME) durante 6 meses de acompanhamento. Projeto: Estudo prospectivo intervencionista, randomizado e controlado. Métodos: Sessenta olhos de 30 pacientes com RDP bilateral precoce foram randomizados para o grupo de estudo (GE) que foram tratados com PFC associado a duas injeções de RBZ intravítreo (0.5mg/0.05ml) ou para o grupo controle (GC) tratados apenas com PFC. Mudanças na acuidade visual (AV) corrigida, na sensibilidade ao contraste (SC) e na espessura foveal (EF) foram comparados no início, e nos 1, 3 e 6 meses após o tratamento. Resultados: No GE, a diferença na média da AV do baseline para o mês 6 teve um aumento significativo de + 3,4 letras (p = 0,006) e uma diminuição significativa na EF de - 47.6um (p < 0,001). No GC, a diferença na média da AV teve uma diminuição de - 3,4 letras (p = 0,04) e uma mudança na EF de -3.8 um (p = 0,96). Com relação ao teste de SC dentre os 28 olhos do GE, houve uma melhora no mês 6 em relação ao baseline nos ciclos: 1,5 (p < 0.001) e 3,0 ciclo (p=0.023). Dentre os 30 olhos do GC, não houve uma diferença estatística nos momentos estudados. Conclusão: A injeção intravítrea de RBZ associado com PFC pode ser um tratamento eficaz em olhos de pacientes com RDP precoce e EMD / Purpose: To compare the efficacy of therapy with panretinal photocoagulation (PRP) and intravitreal ranibizumab (RBZ) injection versus PRP alone in patients with treatment-naive bilateral non-high risk proliferative diabetic retinopathy (PDR) with and without diabetic macular edema (DME) with a 6-month follow-up. Design: Prospective, interventional, randomized controlled trial. Methods: Sixty eyes of 30 patients with bilateral non-high risk PDR were randomized either to the study group (SG) receiving PRP plus two intravitreal ranibizumab injections (0.5mg/0.05ml), the first one week before and the second four weeks after the PRP or to the control group (CG) receiving PRP alone. Mean change in best-corrected visual acuity (BCVA), contrast sensitivity (CS) and central macular thickness (CMT) were compared at baseline and 1, 3 and 6 months after treatment. Results: Changes from baseline to 6 months showed in the SG an increased in the BCVA by + 3.4 letters (p= 0.006) with a decrease in CMT by - 47.6um (p < 0.001). In the CG, a decrease by - 3.4 letters (p = 0.04) and an decrease by -3.8um (p= 0.96). Regarding the CS in the SG, there was an improvement compared to baseline for the sixth month in the 1.5 (p < 0.001) and 3.0 cycles (p = 0.023). The CG did not show significant results from baseline to month 6. Conclusion: Intravitreal RBZ associated with PRP can be an effective treatment in eyes with non-high risk PDR and DME

INTRODUÇÃO: O presente estudo avaliou o tratamento com injeções intravítreas de Bevacizumabe (IVB) associadas à panfotocoagulação (PFC) da retina na retinopatia diabética proliferativa (RDP) de alto risco com ou sem edema macular (EM). MÉTODOS: Ensaio clínico randomizado, prospectivo, aberto e mascarado composto por pacientes com Diabetes melitos (DM) tipo 2. A acuidade visual (AV) foi medida com a tabela Early Treatment Diabetic Retinopathy Study e a sensibilidade ao contraste (SC) pela da tabela Vistech Consultants Incorporation 6500. Os pacientes foram submetidos a exame de angiofluoresceinografia para observação de neovascularização retiniana e isquemia macular e à tomografia de coerência óptica (OCT), para se obter a espessura foveal (EF) e o volume macular (VM). Após os exames, um dos olhos do mesmo paciente foi randomizado para realizar somente PFC, grupo controle (GC), e o outro para PFC associado a injeções IVB, grupo de estudo (GE). A hemorragia vítrea (HV) e a presença de complicações também foram avaliadas. RESULTADOS: Dos 42 pacientes incluídos, 35 completaram o estudo. A média de idade foi de 56±8 anos, com predominância do gênero masculino 21 (60%). Vinte e seis (74%) pacientes eram portadores de Hipertensão Arterial Sistêmica com média de duração de 9±10 anos. A média de duração do DM foi de 18±9 anos sendo 23 (66%) usuários de insulina e 21 (68,5%), fácicos. A AV e a SC não demonstraram diferença entre os grupos no total da amostra. O GE demonstrou melhora em comparação ao GC na EF no 1º mês, e no VM nos 1° e 3º meses de seguimento. Quanto aos 12 pacientes com EM bilateral somente a EF demonstrou redução no GE no 1º mês de seguimento. Ao se avaliar os grupos separadamente, o GC apresentou agravamento da AV e SC durante todo seguimento. Houve também aumento da EF nos 1º e 6º meses e VM nos 1º , 3º e 6º meses de seguimento. O GE demonstrou estabilização da AV, SC, EF e VM. Correlacionado às funções visuais, AV com a SC, toda vez que houve piora da AV esta foi acompanhada pelo agravamento da SC em todos os momentos no GC e GE. Quando correlacionadas as AV e SC com as EF e VM, toda vez que a espessura macular aumentava, havia piora da função visual. Dos sete pacientes excluídos do estudo por apresentarem HV, cinco integravam o GC e dois o GE. Não houve aparecimento de catarata, endoftalmite e/ou aumento significativo da pressão ocular. CONCLUSÃO: Na RDP de alto risco, o uso adjuvante de injeções intravítreas de Bevacizumabe associadas à panfotocoagulação da retina pode estabilizar a AV, SC, EF e VM, diminuir a incidência de HV e reduzir a da espessura macular. Em relação à correlação entre as variáveis, quando houve piora da AV, esta foi acompanhada da piora da SC e o aumento da EF e VM causaram piora da AV e SC / INTRODUCTION: This study evaluated the treatment with intravitreal injections of Bevacizumab (IVB) associated with panretinal photocoagulation (PRP) in high-risk proliferative diabetic retinopathy (PDR) with or without diabetic macular edema (DME). METHODS: Prospective, open and masked, randomized clinical trial, composed of patients with type 2 Diabetes Mellitus (DM). The visual acuity (VA) was measured with the Early Treatment Diabetic Retinopathy Study charts and the contrast sensitivity (CS) through the chart of Vistech Consultants Incorporation 6500. Patients were submitted to a fluorescein angiography examination to observe retinal neovascularization and macular ischemia and to an optical coherence tomography (OCT) to obtain the foveal thickness (FT) and macular volume (MV). After the tests, one of the eyes from the same patient was randomized to realize only the PRP, the control group (CG), and the other for PRP associated to IVB injections, the study group (SG). Vitreous hemorrhage (VH) and presence of complications were also evaluated. RESULTS: Thirty-five of the forty-two patients included, completed the study. The mean age was 56±8 years, with a predominance of 21 (60%) males. Twenty-six (74%) patients had systemic hypertension with a mean duration of 9±10 years. The mean duration of DM was 18±9 years, of which 23 (66%) were insulin users and 21 (68.5%) were phakic. The VA and CS showed no difference between groups in the total sample. The SG showed improvement compared to the CG in FT for the 1st month, and in MV for the 1st and 3rd month of follow-up. As for the 12 patients with bilateral ME, only the FT showed a reduction in the SG for the 1st month of follow-up. When evaluating the groups separately, the CG showed worsening of VA and CS at all times. There was also an increase of FT for the 1st and 6th months and of MV for the 1st, 3rd and 6th month follow-up. The SG showed stabilization of VA, CS, FT and MV. When correlated to visual functions, VA and CS, a worsening of the VA was accompanied every time by a worsening of the CS in both the CG and SG. When VA and CS are correlated to FT and MV, there was worsening of visual function whenever macular thickness increased. Of the seven patients excluded from the study by presenting VH, 5 belonged to the CG and the 2 to the SG. There was no incidence of cataracts, endophthalmitis and/or significant increase in intraocular pressure. CONCLUSION: In high-risk PDR, intraocular injections of Bevacizumab as an adjuvant treatment to PRP, can stabilize VA, CS, FT and MV, reduce of the incidence of VH and decrease the macular thickness. Regarding the correlation between variables, when there was a worsening of VA, this was accompanied by a worsening of the CS, and an increase in FT and MV caused the worsening of the VA and CS