Volatile Blood Pressure Due To Baroreflex and Autonomic Failure

An 85-year-old male was hospitalized because of deterioration of his general condition and infection of the tracheostoma. He had had laryngectomy, bilateral neck dissection and radiation therapy for a laryngeal carcinoma 5 years earlier. Despite a good recovery, he could not get up because of a new onset of postural symptoms (dizziness, lightheadedness, collapse). Late onset of baroreflex failure and autonomic nervous system failure were diagnosed. Volatility of blood pressure (supine hypertension, upright hypotension) was treated with NaCl supplement during the day and a short-acting antihypertensive (clonidine) at night. With this regimen, the patient could walk without support.

Soybean lunasin mediates colon carcinogenesis by inducing apoptosis and preventing outgrowth of metastasis

Colorectal cancer (CRC) is the third most common cancer worldwide. Various factors such as age, lifestyle and dietary patterns affect the risk of having CRC. Epidemiological studies showed a chemopreventive effect of soy consumption against CRC. However, which component(s) of soybean is associated with this reduced risk is not yet fully delineated. The objective of this research was to evaluate the anti-colon cancer potential of lunasin isolated from defatted soybean flour using in vitro and in vivo models of CRC. Lunasin was isolated from defatted soybean flour by a combination of different chromatographic and ultrafiltration techniques. The anti-colon cancer potential of lunasin was determined using different human colon cancer cell lines in vitro and a CRC liver metastasis model in vivo. Lunasin caused cytotoxicity to different human colon cancer cells with an IC50 value of 13.0, 21.6, 26.3 and 61.7 µM for KM12L4, RKO, HCT-116 and HT-29 human colon cancer cells, respectively. This cytotoxicity correlated with the expression of the α5 integrin on human colon cancer cells with a correlation coefficient of 0.78. The mechanism involved in the cytotoxic effect of lunasin was through cell cycle arrest and induction of the mitochondrial pathway of apoptosis. In KM12L4 human colon cancer cells, lunasin caused a G2/M phase arrest increasing the percentage of cells at G2/M phase from 12% (PBS-treated) to 24% (treated with 10 µM lunasin). This arrest was attributed to the capability of lunasin to increase the expression of cyclin dependent kinase inhibitors p21 and p27. At 10 µM, lunasin increased the expression of p21 and p27 in KM12L4 colon cancer cells by 2.2- and 2.3-fold, respectively. Flow cytometric analysis showed that lunasin at 10 µM increased the percentage of cells undergoing apoptosis from 13.6% to 24.7%. This is further supported by fluorescence microscopic analysis of KM12L4 cells treated with 10 µM lunasin showing chromatin condensation and DNA fragmentation. The mechanism involved is through modification of proteins involved in the mitochondrial pathway of apoptosis in KM12L4 cells as 10 µM lunasin reduced the expression of the anti-apoptotic Bcl-2 protein by 2-fold and increased the expression of the pro-apoptotic proteins Bax, cytochrome c and nuclear clusterin by 2.2-, 2.1- and 2.3- fold, respectively. This led to increased expression and activity of the executioner of apoptosis, caspase-3 by 1.8- and 2.3-fold, respectively. This pro-apoptotic property of lunasin can be attributed to its capability to internalize into the cytoplasm and nucleus of colon cancer cells 24 h and 72 h after treatment, respectively. In addition, lunasin mediated metastasis of colon cancer cells in vitro by inhibiting the focal adhesion kinase activation thereby reducing expression of extracellular regulated kinase and nuclear factor kappa B and finally inhibiting migration of colon cancer cells. In KM12L4 colon cancer cells, 10 µM lunasin resulted in the reduction of phosphorylation of focal adhesion kinase and extracellular regulated kinase by 2.5-fold, resulting in the reduced nuclear translocation of p50 and p65 NF-κB subunits by 3.8- and 1.4-fold, respectively. In an in vivo model of CRC liver metastasis, daily intraperitoneal administration of lunasin at 4 mg/kg body weight resulted in the inhibition of KM12L4 liver metastasis as shown by the reduction of the number of liver metastases from 28 (PBS-treated) to 14 (lunasin-treated, P = 0.047) and reduction in tumor burden as measured by liver weight/body weight from 0.13 (PBS-treated) to 0.10 (lunasin-treated, P = 0.039). Moreover, lunasin potentiated the anti-metastatic effect of the chemotherapeutic drug oxaliplatin given at 5 mg/kg body weight twice per week. Lunasin and oxaliplatin combination resulted in a more potent inhibition of outgrowth of KM12L4 cell metastases to the liver reducing the number of liver metastases by 6-fold and reducing the tumor burden in the liver by 3-fold when compared to PBS-treated group. This can be attributed by the capability of lunasin and oxaliplatin to reduce expression of proliferating cell nuclear antigen in liver-tumor tissue as measured by immunohistochemical staining. The results of this research for the first time demonstrated the anti-colon cancer potential of lunasin isolated from defatted soybean flour which might contribute to the chemopreventive effect of soybean in CRC as seen in different epidemiological studies. In conclusion, lunasin isolated from defatted soybean flour mediated colon carcinogenesis by inducing apoptosis and preventing outgrowth of metastasis. We suggest that the results of this research serve as a basis for further study on the chemopreventive effect of lunasin against CRC and a possible adjuvant role for lunasin in therapy of patients with metastatic CRC.

Investigating mushroom LMW compounds as potential Bcl-2 inhibitors: docking studies using AutoDock4

The B cell CLL/lymphoma-2 (Bcl-2) family is functionally classified as either anti-apoptotic or pro-apoptotic, and the regulation of its interactions dictates survival or commitment to apoptosis. Bcl-2 family is also implicated in a wide range of diseases. In some types of cancers, including lymphomas and epithelial cancers, protein overexpression of anti-apoptotic Bcl-2 family, such as the Bcl-2 protein is indicative of cancer in an advanced stage, with a poor prognosis and resistant to chemotherapy [1]. Several reports indicate that mushrooms have the ability to promote apoptosis in tumour cell lines, but the mechanism of action is not fully understood. Inhibition of the interaction between Bcl-2 (anti-apoptotic protein) and proapoptotic proteins could be an important step in the mechanism of mushroom induced apoptosis. Therefore, the discovery of compounds with the capacity to inhibit Bcl-2 is an ongoing research topic on cancer therapy. In this work, docking studies were performed using a dataset of 40 low molecular weight (LMW) compounds present in mushrooms. The docking software AutoDock 4 was used and docking studies were performed using 5 selected Bcl-2 crystal structures as targets. Compounds with the lowest predicted binding energy (predΔG) are expected to be the more potent inhibitors. Among the tested compounds, steroids presented the lowest predΔG with several exhibiting values below -9 kcal/mol. The results are corroborated by several reports that state that steroids induce apoptosis in several tumor cells. It is thus feasible that they might act by preventing Bcl-2 from forming complexes with the respective proapoptotic protein interaction partners, namely Bak, Bax, and Bim. Moreover, previous studies on our research group demonstrated that 48 h treatment of MCF-7 cells (breast carcinoma) with Suillus collinitus methanolic extract caused a decrease in Bcl-2, highlighting the antitumor potential of this mushroom species [2]. In conclusion, the process of apoptosis promoted by mushroom extracts may be related to the inhibition of Bcl-2 by the steroid derivatives herein studied. However, further studies are needed to confirm this hypothesis.

Cancer appetite and symptom questionnaire (CASQ) for brazilian patients: Cross-cultural adaptation and validation study

Background: Appetite and symptoms, conditions generally reported by the patients with cancer, are somewhat challenging for professionals to measure directly in clinical routine (latent conditions). Therefore, specific instruments are required for this purpose. This study aimed to perform a cultural adaptation of the Cancer Appetite and Symptom Questionnaire (CASQ), into Portuguese and evaluate its psychometric properties on a sample of Brazilian cancer patients. Methods: This is a validation study with Brazilian cancer patients. The face, content, and construct (factorial and convergent) validities of the Cancer Appetite and Symptom Questionnaire, the study tool, were estimated. Further, a confirmatory factor analysis (CFA) was conducted. The ratio of chi-square and degrees of freedom (χ2/df), comparative fit index (CFI), goodness of fit index (GFI) and root mean square error of approximation (RMSEA) were used for fit model assessment. In addition, the reliability of the instrument was estimated using the composite reliability (CR) and Cronbach’s alpha coefficient (α), and the invariance of the model in independent samples was estimated by a multigroup analysis (Δχ2). Results: Participants included 1,140 cancer patients with a mean age of 53.95 (SD = 13.25) years; 61.3% were women. After the CFA of the original CASQ structure, 2 items with inadequate factor weights were removed. Four correlations between errors were included to provide adequate fit to the sample (χ2/df = 8.532, CFI = .94, GFI = .95, and RMSEA = .08). The model exhibited a low convergent validity (AVE = .32). The reliability was adequate (CR = .82 α = .82). The refined model showed strong invariance in two independent samples (Δχ2: λ: p = .855; i: p = .824; Res: p = .390). A weak stability was obtained between patients undergoing chemotherapy and radiotherapy (Δχ2: λ: p = .155; i: p < .001; Res: p < .001), and between patients undergoing chemotherapy combined with radiotherapy and palliative care (Δχ2: λ: p = .058; i: p < .001; Res: p < .001). Conclusion: The Portuguese version of the CASQ had good face and construct validity and reliability. However, the CASQ still presented invariance in independent samples of Brazilian patients with cancer. However, the tool has low convergent validity and weak invariance in samples with different treatments.

Experiences of patients undergoing chemotherapy - a qualitative study of adults attending Uganda Cancer Institute

Background: Cancer is a global public health challenge and how patients in countries with poor healthcare infrastructure experience cancer treatment is largely unknown. Purpose: The objective of this study was to describe adult Ugandan cancer patients’ experiences of undergoing chemotherapy treatment. Methodology: Using a qualitative descriptive design, seven in-patients with varying cancer diagnoses at the Uganda Cancer Institute were interviewed about their experiences of undergoing chemotherapy treatment; the interviews were transcribed and analysed thematically. Results: The analysis resulted in nine subthemes, which were categorized under three main themes: ‘experiences related to the body’, with the subthemes dry and sensitive skin, changes in eating and bowel habits, fever and feelings of abnormal body sensation; ‘thoughts and feelings’, with four subthemes reflecting the psychosocial impact of chemotherapy; and ‘actively dealing with discomfort’, with three subthemes describing how patients dealt with side effects, such as by sticking to a diet. Conclusion: Receiving chemotherapy treatment is difficult, and the side effects negatively influenced patients’ bodies and moods. Dealing actively with discomfort and accepting negative impacts in hope of a cure helped the participants manage the acute complications related to the treatment. We recommend the development of interventions to ease discomfort due to chemotherapy.

Bcl-xL (S49) and (S62) sequential phosphorylation/dephosphorylation during mitosis prevents chromosome instability and aneuploidy

Une caractéristique intéressante de la protéine Bcl-xL est la présence d'un domaine en boucle non-structurée entre les hélices α1 and α2 de la protéine. Ce domaine protéique n'est pas essentiel pour sa fonction anti-apoptotique et absent chez CED-9, la protéine orthologue chez Caenorhabditis elegans. A l'intérieur de ce domaine, Bcl-xL subit une phosphorylation et déphosphorylation dynamique sur les résidus Ser49 et Ser62 en phase G2 du cycle cellulaire et lors de la mitose. Lorsque ces résidus sont mutés et les protéines exprimées dans des cellules cancéreuses, les cellules démontrent plusieurs défauts mitotiques liés à l'instabilité chromosomique. Pour analyser les effets de Bcl-xL Ser49 et Ser62 dans les cellules normales, les présentes études ont été réalisées dans des cellules diploïdes humaines normales, et in vivo chez Caenorhabditis elegans. Dans une première étude, nous avons utilisé la lignée cellulaire de cellules fibroblastiques diploïdes humaines normales BJ, exprimant Bcl-xL (type sauvage), (S49A), (S49D), (S62A), (S62D) et les double (S49/62A) et (S49/62D) mutants. Les cellules exprimant les mutants de phosphorylation ont montré des cinétiques de doublement de la population cellulaire réduites. Ces effets sur la cinétique de doublement de la population cellulaire corrèle avec l'apparition de la sénescence cellulaire, sans impact sur les taux de mort cellulaire. Ces cellules sénescentes affichent des phénotypes typiques de sénescence associés notamment à haut niveau de l'activité β-galactosidase associée à la sénescence, la sécrétion d' interleukine-6, l'activation de p53 et de p21WAF1/ Cip1, un inhibiteur des complexes kinase cycline-dépendant, ainsi que la formation de foyers de chromatine nucléaire associés à γH2A.X. Les analyses de fluorescence par hybridation in situ et des caryotypes par coloration au Giemsa ont révélé que l'expression des mutants de phosphorylation de Bcl-xL provoquent de l'instabilité chromosomique et l'aneuploïdie. Ces résultats suggèrent que les cycles de phosphorylation et déphosphorylation dynamiques de Bcl-xL Ser49 et Ser62 sont importants dans le maintien de l'intégrité des chromosomes lors de la mitose dans les cellules normales. Dans une deuxième étude, nous avons entrepris des expériences chez Caenorhabditis elegans pour comprendre l'importance des résidus Ser49 et Ser62 de Bcl-xL in vivo. Les vers transgéniques portant les mutations de Bcl-xL (S49A, S62A, S49D, S62D et S49/62A) ont été générés et leurs effets ont été analysés sur les cellules germinales des jeunes vers adultes. Les vers portant les mutations de Bcl-xL ont montré une diminution de ponte et d'éclosion des oeufs, des variations de la longueur de leurs régions mitotiques et des zones de transition, des anomalies chromosomiques à leur stade de diplotène, et une augmentation de l'apoptose des cellules germinales. Certaines de ces souches transgéniques, en particulier les variants Ser/Ala, ont également montré des variations de durée de vie par rapport aux vers témoins. Ces observations in vivo ont confirmé l'importance de Ser49 et Ser62 à l'intérieur du domaine à boucle de Bcl-xL pour le maintien de la stabilité chromosomique. Ces études auront une incidence sur les futures stratégies visant à développer et à identifier des composés qui pourraient cibler non seulement le domaine anti-apoptotique de la protéine Bcl-xL, mais aussi son domaine mitotique pour la thérapie du cancer.

Anticorpos bloqueadores dos checkpoints imunes

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Triptolide induces cell apoptosis in human stomach cancer cell via caspase 3-dependent cascade pathway

Purpose: To evaluate the effect of triptolide on the induction of cell apoptosis in human gastric cancer BGC-823 cells. Methods: The cytotoxicity of triptolide was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT) assay. The effect of triptolide on cell proliferation was measured using lactate dehydrogenase (LDH) assay. Cell apoptosis was determined by Annexin V/propidium iodide (PI) double-staining assay. Results: MTT results indicate that triptolide significantly decreased cancer cell numbers in dose- and time-dependent manners in MTT assay. Data from LDH assay showed that triptolide markedly induced cytotoxicity in gastric cancer cells. Triptolide also remarkably induced both early and late apoptotic process in BGC-823 cells. In addition, the compound down-regulated the expression of anti-apoptotic Bcell lymphoma-2 (bcl-2) and up-regulated the expression of pro-apoptotic BCL-2-associated X (bax) in a dose-dependent manner. Furthermore, the pro-apoptotic activity of triptolide was involved in the activation of caspase-3 pathway in BGC-823 cells. Conclusion: Taken together, the findings strongly indicates that the pro-apoptotic activity of triptolide is regulated by caspase 3-dependent cascade pathway, and thus needs to be further developed for cancer therapy.

Probing the biophysical interaction between Neocarzinostatin toxin and EpCAM RNA aptamer

Neocarzinostatin (NCS) a potent DNA-damaging, anti-tumor toxin extracted from Streptomyces carzinostaticus that recognizes double-stranded DNA bulge and induces DNA damage. 2 Fluoro (2F) Modified EpCAM RNA aptamer is a 23-mer that targets EpCAM protein, expressed on the surface of epithelial tumor cells. Understanding the interaction between NCS and the ligand is important for carrying out the targeted tumor therapy. In this study, we have investigated the biophysical interactions between NCS and 2-fluro Modified EpCAM RNA aptamer using Circular Dichroism (CD) and Infra-Red (IR) spectroscopy. The aromatic amino acid residues spanning the β sheets of NCS are found to participate in intermolecular interactions with 2 F Modified EpCAM RNA aptamer. In-silico modeling and simulation studies corroborate with CD spectra data. Furthermore, it reinforces the involvement of C and D1 strand of NCS in intermolecular interactions with EpCAM RNA aptamer. This the first report on interactions involved in the stabilization of NCS-EpCAM aptamer complex and will aid in the development of therapeutic modalities towards targeted cancer therapy.

Controllable drug uptake and nongenomic response through estrogen-anchored cyclodextrin drug complex

Breast cancer is a leading killer of women worldwide. Cyclodextrin-based estrogen receptor-targeting drug-delivery systems represent a promising direction in cancer therapy but have rarely been investigated. To seek new targeting therapies for membrane estrogen receptor-positive breast cancer, an estrogen-anchored cyclodextrin encapsulating a doxorubicin derivative Ada-DOX (CDE1-Ada-DOX) has been synthesized and evaluated in human breast cancer MCF-7 cells. First, we synthesized estrone-conjugated cyclodextrin (CDE1), which formed the complex CDE1-Ada-DOX via molecular recognition with the derivative adamantane-doxorubicin (Ada-DOX) (Kd =1,617 M(-1)). The structure of the targeting vector CDE1 was fully characterized using (1)H- and (13)C-nuclear magnetic resonance, mass spectrometry, and electron microscopy. CDE1-Ada-DOX showed two-phase drug-release kinetics with much slower release than Ada-DOX. The fluorescence polarization analysis reveals that CDE1-Ada-DOX binds to recombinant human estrogen receptor α fragments with a Kd of 0.027 µM. Competition assay of the drug complex with estrogen ligands demonstrated that estrone and tamoxifen competed with CDE1-Ada-DOX for membrane estrogen receptor binding in MCF-7 cells. Intermolecular self-assembly of CDE1 molecules were observed, showing tail-in-bucket and wire-like structures confirmed by transmission electronic microscopy. CDE1-Ada-DOX had an unexpected lower drug uptake (when the host-guest ratio was >1) than non-targeting drugs in MCF-7 cells due to ensconced ligands in cyclodextrins cavities resulting from the intermolecular self-assembly. The uptake of CDE1-Ada-DOX was significantly increased when the host-guest ratio was adjusted to be less than half at the concentration of CDE1 over 5 µM due to the release of the estrone residues. CDE1 elicited rapid activation of mitogen-activated protein kinases (p44/42 MAPK, Erk1/2) in minutes through phosphorylation of Thr202/Tyr204 in MCF-7 cells. These results demonstrate a targeted therapeutics delivery of CDE1-Ada-DOX to breast cancer cells in a controlled manner and that the drug vector CDE1 can potentially be employed as a molecular tool to differentiate nongenomic from genomic mechanism.

Tailored mesoporous silica nanoparticles for controlled drug delivery: platform fabrication, targeted delivery, and computational design and analysis

Mesoporous silica nanoparticles (MSNs) are exceptionally promising drug carriers for controlled drug delivery systems because their morphology, pore structure, pore volume and pore size can be well tailored to obtain certain drug release profiles. Moreover, they possess the ability to specifically transport and deliver anti-cancer drugs when targeting molecules are properly grafted onto their surface. MSNs based drug delivery systems have the potential to revolutionize cancer therapy. This review provides a comprehensive overview of the fabrication, modification of MSNs and their applications in tumour-targeted delivery. In addition, the characterization and analysis of MSNs with computer aided strategies were described. The existing issues and future prospective concerning the applications of MSNs as drug carriers for controlled drug delivery systems were discussed.

Theranostic multimodular potential of zinc-doped ferrite-saturated metal-binding protein-loaded novel nanocapsules in cancers

The present study successfully developed orally deliverable multimodular zinc (Zn) iron oxide (Fe3O4)-saturated bovine lactoferrin (bLf)-loaded polymeric nanocapsules (NCs), and evaluated their theranostic potential (antitumor efficacy, magnetophotothermal efficacy and imaging capability) in an in vivo human xenograft CpG-island methylator phenotype (CIMP)-1(+)/CIMP2(-)/chromosome instability-positive colonic adenocarcinoma (Caco2) and claudin-low, triple-negative (ER(-)/PR(-)/HER2(-); MDA-MB-231) breast cancer model. Mice fed orally on the Zn-Fe-bLf NC diet showed downregulation in tumor volume and complete regression in tumor volume after 45 days of feeding. In human xenograft colon cancer, vehicle-control NC diet-group (n=5) mice showed a tumor volume of 52.28±11.55 mm(3), and Zn-Fe-bLf NC diet (n=5)-treated mice had a tumor-volume of 0.10±0.073 mm(3). In the human xenograft breast cancer model, Zn-Fe-bLf NC diet (n=5)-treated mice showed a tumor volume of 0.051±0.062 mm(3) within 40 days of feeding. Live mouse imaging conducted by near-infrared fluorescence imaging of Zn-Fe-bLf NCs showed tumor site-specific localization and regression of colon and breast tumor volume. Ex vivo fluorescence-imaging analysis of the vital organs of mice exhibited sparse localization patterns of Zn-Fe-bLf NCs and also confirmed tumor-specific selective localization patterns of Zn-Fe-bLf NCs. Dual imaging using magnetic resonance imaging and computerized tomography scans revealed an unprecedented theranostic ability of the Zn-Fe-bLf NCs. These observations warrant consideration of multimodular Zn-Fe-bLf NCs for real-time cancer imaging and simultaneous cancer-targeted therapy.

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations.

Eficacia de terapias biológicas de tipo anti-angiogénico en el cáncer colorrectal metastásico revisión sistemática de la literatura

Introducción: El cáncer colorrectal (CCR) se encuentra entre los 5 tipos de cáncer con mayor incidencia a nivel mundial. Alrededor del 20% de los casos son diagnosticados en estadios metastásico, donde el tratamiento inicialmente era quimioterapia con una supervivencia global a 5 años de 12 a 14 meses. Es así que se investiga el papel de la angiogénesis tumoral, orientado al desarrollo de terapias, implementando su uso en estadios avanzados. Metodología: Se realizó una búsqueda sistemática en las bases de datos Embase, PubMed, SciELO y LILIACS con términos estandarizados a través de la herramienta MeSH y DECS bajo los lineamientos establecidos en las guías de revisiones sistemáticas y meta-análisis (Manual Cochrane). Se tomaron estudios clínicos aleatorizados controlados con pacientes con CCR metastásico, que hayan recibido quimioterapia sola o combinada con terapias antiangiogénicas, publicados en inglés y español entre el 2003 y 2013. Resultados: 6 artículos cumplieron con criterios de inclusión. Estos reportaron 15.8 meses en promedio de supervivencia global en el tratamiento de quimioterapia asociada a terapias biológicas frente a 14.4 meses con solo quimioterapia. Los eventos adversos de tipo vascular aumentaron más en el grupo de antiangiogénicos, reportando muertes debidas a perforaciones intestinales. Conclusiones: Los regímenes de quimioterapia asociadas a terapias antiangiogénicas brindan una mayor supervivencia global y libre de progresión, al igual que mayor número de tasas de respuesta. Son terapias con eventos adversos importantes pero que deberá seleccionarse bien al paciente para disminuir su riesgo de eventos. Palabras claves: Cáncer colorrectal metastásico, terapia anti-angiogénica, quimioterapia en segunda línea, receptor del factor de crecimiento de endotelio vascular, supervivencia global.