Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Anti-angiogenesis in Lung Cancer: Current Situation, Progress and Confusion / 中国肺癌杂志

Lung cancer is a highly vascular tumors, over the past ten years, anti-angiogenes is has been proved to be an effective and highly promising combinational treatment. The data of the combination of anti-angiogenesis with chemotherapy, targeted therapy, immunotherapy has been constantly updating. Advanced lung cancer patients, no matter different groups or different stages of the disease, are benefited from anti-angiogenes. In this paper, based on the clinical status and unsolved problems, combined with the latest clinical and translational research data, we reviewed the current anti-angiogenesis treatment of lung cancer.
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Effects of components in stasis-resolving and collateral-dredging Chinese herbal medicines on angiogenesis and inflammatory response of human umbilical vein endothelial cells induced by VEGF / 中国中药杂志

The present study investigated the mechanism of components in stasis-resolving and collateral-dredging Chinese herbal medicines, including scutellarin(Scu), paeonol(Pae), and hydroxy safflower yellow A(HSYA), in the treatment of psoriasis by regulating angiogenesis and inflammation. The human umbilical vein endothelial cells(HUVECs) cultured in vitro were divided into a normal group, a model group, a VEGFR tyrosine kinase inhibitor Ⅱ(VRI) group, and Scu, Pae, and HSYA groups with low, me-dium, and high doses. Cell viability was detected by the CCK-8 assay. Cell migration was detected by wound healing assay. Tube formation assay was used to measure the tube formation ability. Western blot was used to detect the protein expression of the VEGFR2/Akt/ERK1/2 signaling pathway. The secretion levels of inflammatory cytokines IFN-γ, IL-1β, IL-6, and TNF-α were detected by ELISA. The results showed that compared with the model group, all the Scu, Pae, and HSYA groups could reduce cell viability, inhibit cell migration and tube formation(P<0.05, P<0.01), and down-regulated the protein expression of VEGFR2, p-VEGFR2, Akt, p-Akt, ERK1/2, and p-ERK1/2. Scu and Pae could down-regulate VEGFR2 expression(P<0.05, P<0.01), while other groups only showed a downward trend. Scu and Pae significantly reduced IFN-γ and IL-6 levels(P<0.01), and HSYA significantly reduced the levels of IFN-γ, IL-1β, and IL-6(P<0.01). Scu, Pae, and HSYA had no significant effect on TNF-α. The results suggested that Scu, Pae, and HSYA may exert a therapeutic role in psoriasis-related angiogenesis and inflammation by inhibiting VEGFR2/Akt/ERK1/2 signaling pathway and inhibiting the secretion of IFN-γ, IL-1β, and IL-6.

Red propolis and L-lysine on angiogenesis and tumor growth in a new model of hamster cheek pouch inoculated with Walker 256 tumor cells / Própolis vermelha e L-lisina na angiogênese e no crescimento tumoral em novo modelo de bolsa jugal de hamster inoculada com células de tumor de Walker 256

ABSTRACT Objective: To evaluate the effect of red propolis and L-lysine on angiogenesis and tumor growth in a new model of hamster cheek pouch inoculated with Walker 256 tumor cells. Methods: The study consisted of two experiments with four groups each (total: 57 hamsters). In the experiment 1, the animals were inoculated with Walker tumor cells, followed by administration of test substances (red propolis 200mg/5mL/kg or L-lysine 150mg/kg) or control substances (gum arabic 5mL/kg or water 5mL/kg) for 10 days. The animals in the experiment 2 received red propolis, L-lysine, gum arabic or water at the same doses, for 33 days prior to inoculation of Walker tumor cells, followed by 10 days of treatment with the same substances. Based on single-plane images, angiogenesis was quantified (mean vascular area), in percentage, and tumor area (mm2) and perimeter (mm). Results: In the experiment 1, compared to animals receiving water, the mean vascular area expressed in percentage was significantly smaller in animal treated with propolis (p<0.05) and L-lysine (p<0.001). Conclusion: Both red propolis and L-lysine inhibited tumor angiogenesis in the new hamster cheek pouch model when administered after tumor inoculation.

RESUMO Objetivo: Avaliar o efeito da própolis vermelha e da L-lisina na angiogênese e no crescimento tumoral em novo modelo de bolsa jugal de hamster inoculada com células de tumor de Walker 256. Métodos: O estudo consistiu em dois experimentos com quatro grupos cada (total: 57 hamsters). No experimento 1, os animais foram inoculados com células de tumor de Walker, tendo em seguida administradas as substâncias teste (própolis vermelha 200mg/5mL/kg ou L-lisina 150mg/kg) ou controle (goma arábica 5mL/kg ou água 5mL/kg) por 10 dias. Os animais do experimento 2 receberam própolis vermelha, L-lisina, goma arábica ou água nas mesmas doses, por 33 dias antes do inóculo das células de tumor de Walker, seguido por 10 dias de tratamento com as mesmas substâncias. Baseado em imagens em plano único, foram quantificados a angiogênese (área vascular média), em termos percentuais, e a área (mm2) e o perímetro (mm) do tumor. Resultados: Comparada aos animais que receberam água, a área vascular média, expressa em percentagem, foi significativamente menor nos animais tratados com própolis (p<0,05) e com L-lisina (p<0,001). Conclusão: Tanto a própolis vermelha quanto a L-lisina inibiram a angiogênese no novo modelo de bolsa jugal de hamsters, quando administradas após a inoculação do tumor.

Effect of red propolis on hamster cheek pouch angiogenesis in a new sponge implant model

Abstract Purpose: To evaluate the effects of red propolis on cheek pouch angiogenesis in a hamster new model sponge implant. Methods: Forty eight animals divided into eight groups. (Groups I-IV), the animals were treated for 15 days before and 10 days after sponge implantation. (Groups V-VIII), the animals were treated for 10 days after sponge implantation (GI and GV: red propolis 100 mg/kg, GII and GVI: celecoxib 20 mg/kg, GIII and GVII: 1% gum arabic 5 mL/kg, GIV and GVIII: distilled water 5 mL/kg). On the 11th day of implantation, the animals were anesthetized for stereoscopic microscopic imaging and morphometric quantification of angiogenesis (SQAN), followed by histopathological evaluation (H&E). Results: In the SQAN analysis, no significant difference was found between the groups. However, on histology, propolis was found reduce the population of mastocytes in the qualitative analyses (p = 0,013) in the quantitative analyses to reduce the number of blood vessels (p = 0,007), and increase the macrophage count (p = 0,001). Conclusion: Red propolis inhibited inflammatory angiogenesis when administered before andcontinuously after sponge implant, and was shown to have immunomodulating effects on inflammatory cells (mastocytes and macrophages) in a new sponge implant hamster model.

Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

Platelet activating factor is a lipid mediator of inflammation, and in recent decades, it has emerged as an important factor in tumor outcomes. Platelet activating factor acts by specific binding to its receptor, which is present in both tumor cells and cells that infiltrate tumors. Pro-tumorigenic effects of platelet activating factor receptor in tumors includes promotion of tumor cell proliferation, production of survival signals, migration of vascular cells and formation of new vessels and stimulation of dendritic cells and macrophages suppressor phenotype. In experimental models, blocking of platelet activating factor receptor reduced tumor growth and increased animal survival. During chemotherapy and radiotherapy, tumor cells that survive treatment undergo accelerated proliferation, a phenomenon known as tumor cell repopulation. Work from our group and others showed that these treatments induce overproduction of platelet activating factor-like molecules and increase expression of its receptor in tumor cells. In this scenario, antagonists of platelet activating factor markedly reduced tumor repopulation. Here, we note that combining chemo- and radiotherapy with platelet activating factor antagonists could be a promising strategy for cancer treatment.

Angiogenesis and tumor progression inhibition of cyclooxygenase-2 selective inhibitor celecoxib associated with poly (lactic-co-glycolic acid) in tumor cell line resistant to chemotherapy / Inhibición de angiogénesis y progresión tumoral por inhibidor selectivo de ciclooxigenasa-2 celecoxib asociado con ácido (poli láctico co-glicólico) en línea de células tumorales resistentes a quimioterapia

Although, antineoplastic therapies have now been developed reduction of tumor progression,itis necessarytofind new therapeutic alternatives to suppress angiogenesis.Thus celecoxib (Cx) has been used for its antiangiogenic action in combination with certain polymeric compounds such as poly (lactic co-glycolic acid) (PLGA) acid, which help to improve the bioavailability and avoid effects of long drug administrations. For this purpose we used a murine tumor modelinduced by mammary adenocarcinoma cells resistant to chemotherapy (TA3-MTXR). CX/PLGA inhibits the microvascular density, VEGF expression and cell proliferationinaddition to increased apoptosis (P <0.0001). Cx reduces tumor progression in a concentration of 1000 ppm associated with PLGA, reducing cell proliferation, the presence of VEGF and promoting apoptosis of multiresistant TA3 tumor cells.

Si bien actualmente se han desarrollado terapias antineoplásicas que permiten reducir de cierta manera el avance tumoral, es necesario buscar nuevas alternativas terapéuticas que permitan suprimir la angiogénesis. Es así como el Celecoxib (Cx) ha sido utilizado por su acción antiangiogénica en combinación con algunos compuestos poliméricos, tal como el ácido poli (láctico co-glicólico) (PLGA), el cual ayudaría a mejorar la biodisponibilidad y evitaría efectos derivados de largas administraciones del fármaco. Para tal efecto se ha utilizado un modelo tumoral murino, inducido por células tumorales de adenocarcinoma mamario resistente a la quimioterapia (TA3-MTXR). Los resultados indican que CX/PLGA inhibe la microvascularización, expresión de VEGF y la proliferación celular además del aumento de la apoptosis (P<0,0001). El efecto antitumoral del Cx está bien reportado en la literatura; este sumado a la microencapsulación con PLGA, aportarían un sistema de administración útil, ya que nos otorga una administración sostenida en el tiempo, los cual podría ayudar a mantener los niveles de droga durante un período más prolongado, lo cual sería beneficioso en la terapia tumoral.

Celecoxib/PLGA suprime angiogénesis y metástasis pulmonar de un cáncer mamario murino experimental / Celecoxib/PLGA suppresses angiogenesis and lung metastasis of murine experimental breast cancer

La angiogénesis y metástasis son eventos esenciales en el proceso de invasión tumoral. Su relación íntima los hace buenos blancos en la terapia antitumoral. El objetivo fue analizar el patrón de metástasis pulmonar y angiogénesis, luego de la aplicación del antiangiogénico Celecoxib microencapsulado en ácido poli(láctico-co-glicólico) en ratones. Se utilizó un modelo de tumor experimental, inducido por células TA3-MTX-R, en 18 ratones, separados en 3 grupos de 6 animales, los cuales fueron tratados con dos presentaciones de Celecoxib en administración intramuscular (Grupo Control; Grupo Cx 1000 ppm y Grupo Cx 1000 ppm+PLGA). Los ratones fueron sacrificados y procesados histológicamente para ser teñidos con H&E y Tricrómico de Arteta. El estudio reveló que el pulmón muestra una marcada heterogeneidad, y un patrón de metástasis perivascular; además, Celecoxib asociado a ácido poli(láctico-co-glicólico) redujo la invasión tumoral y angiogénesis en el pulmón. Los resultados son similares a descripciones parciales realizadas previamente y son comparables a otras líneas tumorales, siendo celecoxib/ácido poli(láctico-co-glicólico) un candidato potencial en la terapia antitumoral.

Angiogenesis and metastasis are critical events on the tumor invasion process. Their close association is related as a good target in antitumor therapy. The aim was to analyze lung metastasis pattern and angiogenesis following application of microencapsulated Celecoxib with poli(lactic-co-glycolic) acid in mice. An experimental tumor model was assessed, induced by TA3-MTX-R cells, in 18 mice, separated in 3 groups of 6 animals and treated with 2 intramuscular Celecoxib presentations (Group Control; Group Cx 1000 ppm and Group Cx 1000 ppm+PLGA). Mice were sacrificed and histologically processed to stain slides with H&E and Arteta Trichromic. The study revealed that the lung showed a significant heterogeneity, and a perivascular metastasis pattern; moreover, Celecoxib associated to poli(lactic-co-glycolic) acid reduces tumor invasion and pulmonary angiogenesis. The results are similar to partial previous descriptions and are comparable to other tumor lines, concluding that Celecoxib/poli(lactic-co-glycolic) acid is a potential candidate in antitumor therapy.

Quercetin alleviates pulmonary angiogenesis in a rat model of hepatopulmonary syndrome

Quercetin shows protective effects against hepatopulmonary syndrome (HPS), as demonstrated in a rat model. However, whether these effects involve pulmonary vascular angiogenesis in HPS remains unclear. Therefore, this study aimed to assess the effect of quercetin on pulmonary vascular angiogenesis and explore the underlying mechanisms. Male Sprague-Dawley rats weighing 200-250 g underwent sham operation or common bile duct ligation (CBDL). Two weeks after surgery, HIF-1α and NFκB levels were assessed in rat lung tissue by immunohistochemistry and western blot. Then, CBDL and sham-operated rats were further divided into 2 subgroups each to receive intraperitoneal administration of quercetin (50 mg/kg daily) or 0.2% Tween for two weeks: Sham (Sham+Tween; n=8), CBDL (CBDL+Tween; n=8), Q (Sham+quercetin; n=8), and CBDL+Q (CBDL+quercetin; n=8). After treatment, lung tissue specimens were assessed for protein (immunohistochemistry and western blot) and/or gene expression (quantitative real-time PCR) levels of relevant disease markers, including VEGFA, VEGFR2, Akt/p-Akt, HIF-1α, vWf, and IκB/p-IκB. Finally, arterial blood was analyzed for alveolar arterial oxygen pressure gradient (AaPO2). Two weeks after CBDL, HIF-1α expression in the lung decreased, but was gradually restored at four weeks. Treatment with quercetin did not significantly alter HIF-1α levels, but did reduce AaPO2 as well as lung tissue NF-κB activity, VEGFA gene and protein levels, Akt activity, and angiogenesis. Although hypoxia is an important feature in HPS, our findings suggest that HIF-1α was not the main cause for the VEGFA increase. Interestingly, quercetin inhibited pulmonary vascular angiogenesis in rats with HPS, with involvement of Akt/NF-κB and VEGFA/VEGFR-2 pathways.

Histological changes caused by meclofenamic acid in androgen independent prostate cancer tumors: evaluation in a mouse model

ABSTRACT Meclofenamic acid is a nonsteroidal anti-inflammatory drug that has shown therapeutic potential for different types of cancers, including androgen-independent prostate neoplasms. The antitumor effect of diverse nonsteroidal anti-inflammatory drugs has been shown to be accompanied by histological and molecular changes that are responsible for this beneficial effect. The objective of the present work was to analyze the histological changes caused by meclofenamic acid in androgen-independent prostate cancer. Tumors were created in a nude mouse model using PC3 cancerous human cells. Meclofenamic acid (10 mg/kg/day; experimental group, n=5) or saline solution (control group, n=5) was administered intraperitoneally for twenty days. Histological analysis was then carried out on the tumors, describing changes in the cellular architecture, fibrosis, and quantification of cellular proliferation and tumor vasculature. Meclofenamic acid causes histological changes that indicate less tumor aggression (less hypercellularity, fewer atypical mitoses, and fewer nuclear polymorphisms), an increase in fibrosis, and reduced cellular proliferation and tumor vascularity. Further studies are needed to evaluate the molecular changes that cause the beneficial and therapeutic effects of meclofenamic acid in androgen-independent prostate cancer.

Antiangiogenic Activity of Acer tegmentosum Maxim Water Extract in Vitro and in Vivo

Angiogenesis, the formation of new blood vessels, is critical for tumor growth and metastasis. Notably, tumors themselves can lead to angiogenesis by inducing vascular endothelial growth factor (VEGF), which is one of the most potent angiogenic factors. Inhibition of angiogenesis is currently perceived as one of the most promising strategies for the blockage of tumor growth. In this study, we investigated the effects of Acer tegmentosum maxim water extract (ATME) on angiogenesis and its underlying signal mechanism. We studied the antiangiogenic activity of ATME by using human umbilical vein endothelial cells (HUVECs). ATME strongly inhibited VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation, as well as vessel sprouting in a rat aortic ring sprouting assay. Moreover, we found that the p44/42 mitogen activated protein (MAP) kinase signaling pathway is involved in the inhibition of angiogenesis by ATME. Moreover, when we performed the in vivo matrigel plug assay, VEGF-induced angiogenesis was potently reduced when compared to that for the control group. Taken together, these results suggest that ATME exhibits potent antiangiogenic activity in vivo and in vitro and that these effects are regulated by the extracellular regulated kinase (ERK) pathway.

Celecoxib decreases growth and angiogenesis and promotes apoptosis in a tumor cell line resistant to chemotherapy

BACKGROUND: During the last few years it has been shown in several laboratories that Celecoxib (Cx), a non-steroidal anti-inflammatory agent (NSAID) normally used for pain and arthritis, mediates antitumor and antiangiogenic effects. However, the effects of this drug on a tumor cell line resistant to chemotherapeutical drugs used in cancer have not been described. Herein we evaluate the angiogenic and antitumor effects of Cx in the development of a drug-resistant mammary adenocarcinoma tumor (TA3-MTXR). RESULTS: Cx reduces angiogenesis in the chick embryonic chorioallantoic membrane assay (CAM), inhibits the growth and microvascular density of the murine TA3-MTXR tumor, reduces microvascular density of tumor metastases, promotes apoptosis and reduces vascular endothelial growth factor (VEGF) production and cell proliferation in the tumor. CONCLUSION: The antiangiogenic and antitumor Cx effects correlate with its activity on other tumor cell lines, suggesting that Prostaglandins (PGs) and VEGF production are involved. These results open the possibility of using Celecoxib combined with other experimental therapies, ideally aiming to get synergic effects.

Metronomic therapy: Chemotherapy revisited.

Cytotoxic antiproliferative chemotherapeutic agents are the mainstay of treatment in cancers. Chemotherapy is usually administered every 2–3 weeks. Along with acute toxicity and long‑term effects of cumulative doses, this strategy potentially allows regrowth of the tumor in the interval period and leads to the emergence of resistant populations of tumor cells. Moreover, even with intense chemotherapy, the outcome is stagnating for most of the tumors. There has been recent interest in the use of chemotherapy in fractionated doses which is far below the maximum tolerated dose. This is called metronomic scheduling of chemotherapy. Here, we review the biology and evidence for metronomic chemotherapy.

Combined blockade of HER2 and VEGF exerts greater growth inhibition of HER2-overexpressing gastric cancer xenografts than individual blockade

Gastric cancer overexpressing the human epidermal growth factor 2 (HER2) protein has a poor outcome, although a combination of chemotherapy and the anti-HER2 antibody trastuzumab has been approved for the treatment of advanced gastric cancer. Vascular endothelial growth factor (VEGF) expression in gastric cancer is correlated with recurrence and poor prognosis; however, the anti-VEGF antibody bevacizumab has shown limited efficacy against gastric cancer in clinical trials. In this study, we evaluated the antitumor effects of trastuzumab; VEGF-Trap binding to VEGF-A, VEGF-B and placental growth factor (PlGF); and a combination of trastuzumab and VEGF-Trap in a gastric cancer xenograft model. Although trastuzumab and VEGF-Trap each moderately inhibited tumor growth, the combination of these agents exerted greater inhibition compared with either agent alone. Immunohistochemical analyses indicated that the reduction in tumor growth was associated with decreased proliferation and increased apoptosis of tumor cells and decreased tumor vascular density. The combined treatment resulted in fewer proliferating tumor cells, more apoptotic cells and reduced tumor vascular density compared with treatment with trastuzumab or VEGF-Trap alone, indicating that trastuzumab and VEGF-Trap had additive inhibitory effects on the tumor growth and angiogenesis of the gastric cancer xenografts. These data suggest that trastuzumab in combination with VEGF-Trap may represent an effective approach to treating HER2-overexpressing gastric cancer.

Angiogenesis inhibition by green propolis and the angiogenic effect of L-lysine on bladder cancer in rats / Inibição da angiogênese pela própolis verde e efeito angiogênico da L-lisina no câncer de bexiga em ratos

PURPOSE: To determine the effects of water-soluble derivative of green propolis in bladder cancer angiogenesis in rats given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN). METHODS: Nine groups were established, where six of them (Groups 1 to 6), the animals received 0.05% BBN in their drinking water for 14 weeks. From the 32nd to the 40th week, Groups 1, 2, 3 and 4 were treated respectively with water, L-lysine (300 mg/kg/day), celecoxib (30 mg/kg/day) and propolis (300 mg/kg/day). Groups 5 and 6 were given propolis and L-lysine from the 1st to the 40th week (150 mg/kg/day). Microvascular density was determined by histological sections stained for the marker CD-31 and analyzed with specific software. RESULTS: The microvascular density in bladder carcinomas was lower (p<0.01) in rats receiving propolis than in controls given carcinogen only. On the other hand, the microvascular density of tumors in rats receiving carcinogen and L-lysine for 40 weeks from the beginning of carcinogen treatment was significantly higher (p<0.01) than in the corresponding controls. CONCLUSION: Water-soluble derivative of propolis inhibits angiogenesis in BBN-induced rat bladder cancer, while L-lysine treatment stimulates angiogenesis if initiated concurrently with BBN.

OBJETIVO: Determinar os efeitos da própolis verde solúvel em água na angiogênese de câncer de bexiga em ratos que receberam n-butil-(-4-hidroxibutil) nitrosamina (BBN). METODOS: Nove grupos foram estabelecidos, onde em seis destes (grupos de 1 a 6) os animais receberam BBN a 0,05% em água de beber por 14 semanas. Na 32ª semana das 40 semanas, os grupos 1, 2, 3 e 4 foram tratados respectivamente com água, L lisina (300 mg/kg/dia), celecoxibe (30 mg/kg/dia) e própolis (300 mg/kg/dia). Os grupos 5 e 6 receberam própolis e L lisina da 1ª a 40ª semana (150 mg/ kg/dia). A densidade microvascular foi determinada por cortes histológicos corados pelo CD-31 e analisados por programa de computador específico. RESULTADOS: A densidade microvascular em carcinomas de bexiga foi menor com p<0,01 nos ratos que receberam própolis do que nos carcinomas do grupo controle que recebeu apenas carcinógeno. Por outro lado, a densidade microvascular de tumores de ratos que receberam carcinógeno e L-Lisina por 40 semanas desde o início do carcinógeno foi significantemente maior com p<0,01 que a densidade microvascular dos tumores de seu respectivo grupo controle. CONCLUSÃO: A própolis verde solúvel em água inibiu a angiogênese em câncer de bexiga induzido pelo BBN, enquanto a L- lisina estimulou a angiogênese quando iniciada juntamente com o BBN.

Inmunomodulación y antiangiogénesis en la terapéutica oncológica: De la investigación básica a la clínica / Immunomodulation and antiangiogenesis in cancer therapy: From basic to clinical research

La investigación básica y pre-clínica en oncología celular y molecular son pilares fundamentales en los que se apoyan la mayoría de los adelantos en la terapéutica del cáncer. Los hallazgos obtenidos y su aplicación en la práctica clínica constituyen la causa del avance sostenido en el tratamiento de la enfermedad neoplásica. El objetivo de este trabajo es resumir y discutir los resultados pre-clínicos en inmunomodulación y anti-angiogénesis para el tratamiento de diversos tipos de tumores, obtenidos en nuestro Instituto durante los últimos 15 años, y la posterior traslación y aplicación del conocimiento experimental en un Ensayo Clínico Fase I/II. Se describen los resultados que contribuyeron a descifrar los mecanismos de acción de la inmunomodulación antimetastásica con ciclofosfamida, la quimioterapia metronómica con diferentes drogas únicas o combinaciones, y finalmente el diseño y resultados preliminares de un ensayo clínico de quimioterapia metronómica para pacientes con cáncer de mama avanzado.

Basic and pre-clinic research in cellular and molecular oncology are the main supports accounting for the advancement in cancer therapeutics. The findings achieved, and their implementation in clinical practice are responsible for the permanent improvement in the treatment of the neoplastic disease. Our present objective is to summarize and discuss the pre-clinical findings in immunomodulation and anti-angiogenesis for the treatment of several types of tumors obtained in our Institute during the last 15 years, and the subsequent translation and application of the acquired experimental knowledge in a Phase I/II Clinical Trial. We present the results and mechanisms of action of antimetastatic immunomodulation with cyclophosphamide, the metronomic chemotherapy with different single drugs and their combinations, and finally the design and preliminary results of a clinical trial with metronomic chemotherapy for patients with advanced breast cancer.

A Case of Ocular Benign Lymphoid Hyperplasia Treated with Bevacizumab Injection

We report the first case of ocular benign lymphoid hyperplasia (BLH) treated with subconjunctival injection of bevacizumab (Avastin). A 27-year-old man presented to our clinic with conjunctival masses and limbal neovascularization. An incisional biopsy yielded the diagnosis of BLH. The patient was subsequently given a subconjunctival injection of bevacizumab (1.25 mg / 0.1 mL). The patient did not experience recurrence or malignant metaplasia during the one-year follow-up period. In patients with conjunctival BLH, subconjunctival injection of bevacizumab can be a useful treatment option in patients unable to undergo a surgical procedure due to limbal neovascularization.

Betamethasone inhibits tumor development, microvessel density and prolongs survival in mice with a multiresistant adenocarcinoma TA3

Tumor resistance to traditional cancer treatments poses an important challenge to modern science. Thus, angiogenesis inhibition is an important emerging cancer treatment. Many drugs are tested and corticosteroids have shown interesting results. Herein we investigate the effect on microvessel density, survival time and tumoral volume of mice with TA3-MTX-R tumors. Twenty six mice were inoculated with lxlO6 tumor cells, 4-5 days after injection, six mice were injected with PBS (group A) and twenty mice were treated with p-met (group B). All animals from Group A died on day 22. Group B was divided into Bl (treated discontinued) and B2 (treated daily) and observed until day 88. All mice were processed for histo-immunohistochemical analysis and the blood vessels were counted. A decrease in microvessel density and tumoral volume and longer survival times were observed in the treated group. We propose that the antiangiogenic p-met effect explains, at least partially, its tumor inhibitory properties. As an important perspective, we will experimentally combine these strategies with those recently described by us with regard to the important antiangiogenic-antitumor effects of Trypanosoma cruzi calreticulin. Since the molecular targets of these strategies are most likely different, additive or synergic effects are envisaged.

Treatment Update on Portal Hypertension and Complications / 대한소화기학회지

Current understanding of the pathophysiology of portal hypertension has resulted in therapeutic approaches aimed at correcting the increased splanchnic blood flow and some of which have been already used in clinical practice. Recently new perspectives opened and erstwhile paradigm has been changed to focus on increased resistance to portal blood flow and the formation of portosystemic collateralization. Several studies revealed the clear-cut mechanisms of hepatic endothelial dysfunction and abnormal angiogenesis contributing to the development of portal hypertension. Thus the modulations of hyperdynamic circulation or angiogenesis seem to be valuable therapeutic targets. In the current review update, we discuss the multidisciplinary management of modulating hepatic vascular resistance and abnormal angiogenesis associated with portal hypertension. However, these new pharmacological approaches are still under investigation and widescale clinical application are needed to develop effective strategies.

Bevacizumab for ocular neovascular diseases: a systematic review / Bevacizumabe para doenças oculares neovasculares: revisão sistemática

CONTEXT AND OBJECTIVE: Many eye diseases involve increased local levels of vascular endothelial growth factor (VEGF), and there are several therapeutic strategies for them. Thus, the aim of this study was to evaluate the effectiveness and safety of bevacizumab for treating eye diseases involving increased local levels of VEGF, as the assumed pathophysiological mechanism. DATA SOURCES: The following databases were systematically searched for evidence: PubMed, CENTRAL (Cochrane Library), Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs) and reference lists, without language restrictions. Only randomized controlled trials were included. The primary outcome of interest was visual acuity, irrespective of the evaluation method. DATA SYNTHESIS: A total of 667 eyes in nine randomized trials were included. Meta-analysis showed that the proportion of patients with age-related macular degeneration who presented improvements from baseline regarding best-corrected visual acuity was higher among those treated with bevacizumab than among those in the photodynamic therapy group (risk ratio, RR, 0.49; 95 percent confidence interval, CI, 0.31 to 0.78; P = 0.01). CONCLUSIONS: The evidence available demonstrates that bevacizumab alone or combined with other treatments is more effective than other options, including photodynamic therapy, focal photocoagulation and triamcinolone. The use of bevacizumab instead of photodynamic therapy could reduce treatment costs by more than 99 percent and could significantly increase access to treatment. However, long-term studies are still needed in order to reduce uncertainty concerning the safety of this medication for all ocular neovascular diseases in which bevacizumab has the potential to improve visual acuity.

CONTEXTO E OBJETIVOS: Muitas doenças oculares envolvem o aumento dos níveis locais de fator de crescimento do endotélio vascular (FCEV), uma diversidade de estratégias terapêuticas para tais condições. Assim, o objetivo do presente estudo é avaliar a efetividade e a segurança de bevacizumabe para o tratamento de pacientes com doença ocular que envolva o aumento dos níveis locais de FCEV, como mecanismo patofisiológico assumido. FONTE DAS INFORMAÇÕES: Foi realizada busca sistemática pelas evidências disponíveis nas seguintes bases de dados da eletrônicas: PubMed, CENTRAL (The Cochrane Library), Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), além de referências bibliográficas de estudos relevantes, sem restrições de língua. Foram incluídos apenas ensaios controlados e aleatórios. Acuidade visual, independentemente do método de avaliação, foi considerada o desfecho primário de interesse. SÍNTESE DOS DADOS: Foi incluído um total de 667 olhos testados em nove ensaios clínicos aleatórios. A metanálise demonstrou que a proporção de pacientes com degeneração macular relacionada à idade que melhoraram a acuidade visual foi maior entre os tratados com bevacizumabe do que entre os pacientes em terapia fotodinâmica (risco relativo [RR] 0.49, 95 por cento intervalo de confiança [IC] 0,31 a 0,78, P = 0,01). CONCLUSÕES: A evidência disponível demonstra que bevacizumabe isolado ou combinado com outras terapias é mais eficaz que terapia fotodinâmica, fotocoagulação focal e triancinolona. O uso de bevacizumabe em vez da terapia fotodinâmica poderia reduzir os custos do tratamento em mais de 99 por cento e aumentar significativamente o acesso ao tratamento. Entretanto, o aspecto de segurança do fármaco ainda necessita ser avaliado por estudos em longo prazo com todas as doenças neovasculares em que bevacizumabe tenha o potencial de melhorar acuidade visual.