RESUMO
For decades, natural products in general and snake venoms (SV) in particular have been a rich source of bioactive compounds for drug discovery, and they remain a promising substrate for therapeutic development. Currently, a handful of SV-based drugs for diagnosis and treatment of various cardiovascular disorders and blood abnormalities are on the market. Likewise, far more SV compounds and their mimetics are under investigation today for diverse therapeutic applications, including antibiotic-resistant bacteria and cancer. In this review, we analyze the state of the art regarding SV-derived compounds with therapeutic potential, focusing on the development of antimicrobial and anticancer drugs. Specifically, information about SV peptides experimentally validated or predicted to act as antimicrobial and anticancer peptides (AMPs and ACPs, respectively) has been collected and analyzed. Their principal activities both in vitro and in vivo, structures, mechanisms of action, and attempts at sequence optimization are discussed in order to highlight their potential as drug leads.
Assuntos
Antibacterianos , Antineoplásicos , Peptídeos , Venenos de Serpentes , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Humanos , Neoplasias/tratamento farmacológico , Peptídeos/administração & dosagem , Peptídeos/química , Venenos de Serpentes/administração & dosagem , Venenos de Serpentes/químicaRESUMO
BACKGROUND: Snake venoms contain various bioactive constituents which possess potential therapeutic effects. The aim of this work was to investigate the effect of the extract from Agkistrodon halys venom on lipopolysaccharide (LPS)-induced myocardial injury. METHODS: Thirty male Sprague-Dawley rats were randomly assigned to three groups (10 rats per group): control group, LPS group and LPS + extract group. Rats in control and the LPS groups were intravenously injected with sterile saline solution, and rats in the LPS + extract group with the extract. After 2 h, rats of the control group were intraperitoneally injected sterile saline solution, and rats in the LPS and the LPS + extract groups were treated with LPS (20 mg per kg body weight). Levels of creatine kinase (CK) and lactate dehydrogenase (LDH) in serum were determined. Anti-inflammation of the extract was analyzed via determination of TNF-α and IL-6 in serum, and expression of TNF-α, IL-6, COX-2 and p-ERK protein in hearts. Heme oxygenase-1 (HO-1) and p-NF-κB protein expression in hearts, superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in serum were used to evaluate the anti-oxidative properties of the extract. RESULTS: Extract pretreatment significantly decreased the level of serum CK and LDH, reduced the generation of inflammatory cytokines such as TNF-α and IL-6, and also reduced serum level of MDA in the LPS + extract group compared with the LPS group. In addition, the extract increased SOD activity in serum, HO-1 protein expression in hearts, and decreased TNF-α, IL-6, COX-2, p-NF-κB and p-ERK1/2 protein expression. CONCLUSION: Our results suggested that beneficial effect of this extract might be associated with an improved anti-oxidation and anti-inflammatory effect via downregulation of NF-κB/COX-2 signaling by activating HO-1/CO in hearts.
Assuntos
Agkistrodon/metabolismo , Traumatismos Cardíacos/prevenção & controle , Lipopolissacarídeos/efeitos adversos , Substâncias Protetoras/administração & dosagem , Venenos de Serpentes/administração & dosagem , Animais , Coração/efeitos dos fármacos , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/genética , Traumatismos Cardíacos/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Malondialdeído/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
Purpose: Tumor cells, with drug resistance, are associated with failed treatment and poor prognosis. Our aim was to explore potential strategy to overcome the epidermal growth factor receptor (EGFR) inhibitors resistance in non-small cell lung cancer (NSCLC).Materials and methods: Flow cytometry was used to examine and sort cells. Using MTT assay, we detected the cell viability under different conditions. Using RT-qPCR and Western blot, we determined the targeted gene expression in mRNA and protein levels. The morphology of the prepared nanoparticles was pictured by transmission electron microscopy. We also performed immunohistochemistry (IHC) and immunofluorescence (IF) to detect the proteins expression. Subcutaneous cancer models in nude mice were constructed to evaluate the anti-cancer effects in vivoResults: Here, we observed enhanced expression of integrin αvß3 in tumor tissues from EGFR inhibitors resistant patients. Also, integrin αvß3-positive NSCLC cells revealed significant EGFR inhibitors resistance, resulting from the activation of Galectin-3/KRAS/RalB/TBK1/NF-κB signaling pathway. Co-encapsulating integrin αvß3 inhibitor and EGFR inhibitor further improved the drug delivery system, leading to superior anti-cancer effects and reduced systemic toxicity.Conclusion: Our results demonstrated that co-encapsulation of erlotinib and cilengitide by MPEG-PLA (Erlo+Cilen/PP) nanoparticles revealed enhanced tumor suppression along with reduced organ damages, providing an innovative approach for NSCLC treatment.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Integrina alfaVbeta3/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Nanopartículas/administração & dosagem , Células A549 , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/administração & dosagem , Feminino , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Venenos de Serpentes/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
PURPOSE: Cancer cells with stem-like phenotype are frequently proliferative and show high resistance to chemotherapeutic agents. Specific cell markers to identify the cancer stem cells and reverse the drugs resistance are urgent needs in clinic cancer treatment. METHODS: To identify the potential role of integrin ß3 in melanoma stem cells. Flow cytometry and immunofluorescence were performed to detect the expression levels of integrin ß3 and integrin ß3 related signal molecules. qRT-PCR and western blotting were used to detect the signaling pathways induced by integrin ß3. Colony formation analysis and melanoma-bearing mice treatment by chemotherapeutic agents and integrin ß3 inhibitors were used to detect the curative effects. RESULTS: We proved that integrin ß3 could serve as a marker of stem-like cancer cells in melanoma, along with the acquired chemotherapeutic drugs resistance. Furthermore, we observed that the membrane-proximal complex of integrin ß3 with KRAS and Galectin-3 on the surface of melanoma cancer cells could recruit the RalB, resulting in the activation of TBK1. The phosphorylated TBK1 facilitates the activation of NF-κB signaling pathway, leading to the stem-like phenotype and drug resistance development in melanoma. Herein, the combination of cilengitide, an integrin ß3 inhibitor, and chemotherapeutic agents were capable of suppressing the tumor growth and reversing the drug resistance induced by integrin ß3. CONCLUSION: These findings identified integrin ß3 as a driver of melanoma stem-like cells with drug resistance and revealed an innovative strategy in clinic melanoma treatment.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Integrina beta3/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Melanoma/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Feminino , Humanos , Integrina beta3/metabolismo , Melanoma/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Venenos de Serpentes/administração & dosagem , Venenos de Serpentes/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Because of our previous preclinical results, we conducted a phase I study associating the specific αvß3/αvß5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer. PATIENTS AND METHODS: A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months. RESULTS: Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively. CONCLUSION: Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Venenos de Serpentes/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/radioterapia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Receptores de Vitronectina/antagonistas & inibidores , Venenos de Serpentes/efeitos adversos , Vinorelbina/administração & dosagemRESUMO
PURPOSE: Cilengitide is a potent and selective inhibitor of the integrins αvß3 and αvß5. The primary objective of this phase I clinical trial was to establish the maximum tolerated dose and determine safety/tolerability of cilengitide in combination with paclitaxel in patients with advanced solid tumors. Secondary objectives included the evaluation of the preliminary clinical outcomes. PATIENTS AND METHODS: Patients with advanced solid tumors experiencing disease progression on standard treatment were assigned to two different dose levels of cilengitide (2000 mg intravenously once or twice weekly) in combination with fixed-dose, weekly paclitaxel (90 mg/m2 intravenously). RESULTS: Twelve evaluable patients were treated per protocol. A single dose limiting toxicity (DLT) of grade 4 neutropenia was observed at the starting dose level of once weekly cilengitide. There were no grade ≥3 adverse events that occurred with >10% frequency. One patient achieved a partial response to therapy. Five patients experienced stable disease as best response, 3 of which discontinued study participation due to progressive, peripheral neuropathy. CONCLUSIONS: Cilengitide in combination with paclitaxel was well tolerated. Antitumor activity was observed. The recommended phase II dose is twice weekly cilengitide (2000 mg) with weekly paclitaxel (90 mg/m2). Further studies evaluating drugs that target this pathway are warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Paclitaxel/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Receptores de Vitronectina/antagonistas & inibidores , Venenos de Serpentes/administração & dosagem , Resultado do TratamentoRESUMO
Children diagnosed with high risk neuroblastoma have poor prognosis which stimulates efforts to broaden therapies of the neoplasm. GD2-ganglioside (GD2) marks neuroblastoma cells and is a target for monoclonal antibodies. We have recently shown that some neuroblastoma cell lines are sensitive to direct cytotoxicity of the anti-GD2 mouse monoclonal antibody 14G2a (mAb). For IMR-32 and LA-N-1 cell lines, treatment with the 14G2a mAb induced evident changes in appearance such as cell rounding, aggregation, loose contact with culture plastic, or detachment. Such findings prompted us to investigate whether modulation of attachment of neuroblastoma cells to extracellular matrix (ECM) proteins can affect their sensitivity to the 14G2a mAb treatment. First, using ultra-low attachment plates, we show that survival of the IMR-32, LA-N-1, LA-N-5, CHP-134 and Kelly cells depends on attachment. Next, we compared cellular ATP levels of the cell lines treated with the 14G2a mAb using uncoated, fibronectin-, collagen IV-coated surfaces to show that the ECM proteins slightly modulate sensitivity of the cell lines to the mAb. Then, we characterized presence of selected integrin subunits or their complexes on the cell surface. Finally, we applied small molecule inhibitors of selected integrin complexes: obtustatin (inhibiting α1ß1 heterodimer), BIO 1211 (inhibiting active α4ß1 heterodimer), cilengitide and SB273005 (inhibitors of αVß3, αVß5 heterodimers) to verify their effects on attachment of cell lines, cellular ATP levels, and in some experiments activities of apoptosis-executing caspase-3 and -7, for the compounds used alone or in combination with the 14G2a mAb. We characterized levels of total FAK (focal adhesion kinase), p-FAK (Tyr397) in IMR-32 cells treated with BIO 1211, and in LA-N-5, Kelly and SK-N-SH cells treated with SB273005. Our results extend knowledge on factors influencing cytotoxicity of 14G2a.
Assuntos
Anticorpos Monoclonais/imunologia , Proteínas da Matriz Extracelular/imunologia , Gangliosídeos/imunologia , Neuroblastoma/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Caspase 3/biossíntese , Linhagem Celular Tumoral , Diterpenos , Gangliosídeos/genética , Humanos , Camundongos , Neuroblastoma/genética , Neuroblastoma/imunologia , Neuroblastoma/patologia , Bibliotecas de Moléculas Pequenas/administração & dosagem , Venenos de Serpentes/administração & dosagemRESUMO
INTRODUCTION: Postoperative cerebral edema is a devastating complication in neurosurgical patients. Loss of blood-brain barrier integrity has been shown to lead to the development of brain edema following neurosurgical procedures. The aim of this study was to evaluate preconditioning with Crotalus helleri venom (Cv-PC) as a potential preventive therapy for reducing postoperative brain edema in the rodent SBI model. C. helleri venom is known to contain phospholipase A2 (PLA2), an enzyme upstream to cyclooxygenase-2 (COX-2) in the inflammatory cascade, acts to increase the production of inflammatory mediators, such as prostaglandins. We hypothesize that Cv-PC will downregulate the response of the COX-2 pathway to injury, thereby reducing the inflammatory response and the development of brain edema after SBI. MATERIALS AND METHODS: 75 male Sprague Dawley rats (280-330g) were divided to the following groups-naïve+vehicle, naïve+Cv-PC, sham, vehicle, Cv-PC, Cv-PC+NS398 (COX-2 inhibitor). Vehicle preconditioned and Cv-PC animals received either three daily subcutaneous doses of saline or C. helleri venom at 72h, 48h, and 24h prior to surgery. In Cv-PC+NS398 animals, NS398 was administered intraperitoneally 1h prior to each Cv-PC injection. Sham-operated animals received craniotomy only, whereas SBI animals received a partial right frontal lobectomy. Neurological testing and brain water content were assessed at 24h and 72h after SBI; COX-2 and PGE2 expression was assessed at 24h postoperatively by Western blot and immunohistochemistry, respectively. RESULTS: At 24h after SBI, the vehicle-treated animals were observed to have increased brain water content (83.1±0.2%) compared to that of sham animals (80.2±0.1%). The brain water content of vehicle-treated animals at 72h post-SBI was elevated at 83.3±0.2%. Cv-PC-treated animals with doses of 10% LD50 had significantly reduced brain water content of 81.92±0.7% and 81.82±0.3% at 24h and 72h, respectively, after SBI compared to that of vehicle-treated animals, while Cv-PC with 5% LD50 doses showed brain water content that trended lower but did not reach statistical significance. At 24h and 72h post-SBI, Cv-PC-treated animals had significantly higher neurological score than vehicle-treated animals. The COX-2 over-expression characterized in SBI was attenuated in Cv-PC-treated animals; NS398 reversed the protective effect of Cv-PC on COX-2 expression. Cv-PC tempered the over-expression of the inflammatory marker PGE2. CONCLUSION: Our findings indicate that Cv-PC may provide a promising therapy for reducing postoperative edema and improving neurological function after neurosurgical procedures.
Assuntos
Edema Encefálico/prevenção & controle , Encéfalo/cirurgia , Lobo Frontal/lesões , Complicações Intraoperatórias/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Complicações Pós-Operatórias/tratamento farmacológico , Venenos de Serpentes/administração & dosagem , Animais , Água Corporal/efeitos dos fármacos , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Edema Encefálico/patologia , Crotalus , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/imunologia , Epiderme/patologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/patologia , Lobo Frontal/cirurgia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Complicações Intraoperatórias/metabolismo , Complicações Intraoperatórias/patologia , Masculino , Procedimentos Neurocirúrgicos , Nitrobenzenos/farmacologia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia , Ratos Sprague-Dawley , Sulfonamidas/farmacologiaRESUMO
BACKGROUND/AIM: To analyze ex vivo effects of combined targeting of the epidermal growth factor-receptor (EGFR) by cetuximab (E) plus αVß3 and αVß5 integrins by cilengitide (Cil) on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines in head and neck squamous cell carcinoma (HNSCC) cells. MATERIALS AND METHODS: Collagenase-IV digests of 43 histopathological confirmed HNSCC cases were seeded into laminin-coated 96-well plates containing E, Cil, or Cil+E in final concentrations of 66.7 µg/ml, 10 µM, and 10 µM+66.7 µg/ml, respectively. Following the FLAVINO-assay protocol, supernatants were harvested after 3 days and adherent cells fixed in ethanol. Counting of CFec was facilitated by FITC-labeled pan-cytokeratin antibodies. Out of 43 HNSCC cases, 39 had adherent growth (mean CFec≥4/well in triplicate controls). Cytokines in supernatants were measured using ELISA were interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and vascular endothelial growth factor A (VEGFA). RESULTS: CFec on laminin was significantly reduced by Cil, E, and Cil+E. Cytokine measurements also revealed significant suppression of MCP-1, IL-6 and VEGFA. The strongest suppression of CFec, MCP-1 and VEGFA release was exerted by Cil and E combined. Efficacy of Cil+E exceeded those of the solely applied pharmaceutics but failed regarding significant synergism of both treatments as E was unable to significantly boost the effects of Cil. In contrast, IL-6 release was significantly suppressed by E but not by Cil, while their combination strongly reduced it. CONCLUSION: Combined targeting of EGFR and integrins with E and Cil heightens their suppressive effects regarding CFec as well as release of pro-angiogenetic and pro-inflammatory cytokines.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Cetuximab/farmacologia , Citocinas/biossíntese , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/imunologia , Venenos de Serpentes/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Cetuximab/administração & dosagem , Quimiocina CCL2/biossíntese , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Interleucina-6/biossíntese , Masculino , Pessoa de Meia-Idade , Venenos de Serpentes/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
BACKGROUND: Envenoming induced by Bothrops snakebites is characterized by drastic local tissue damage that involves an intense inflammatory reaction and local hyperalgesia which are not neutralized by conventional antivenom treatment. Herein, the effectiveness of photobiomodulation to reduce inflammatory hyperalgesia induced by Bothrops moojeni venom (Bmv), as well as the mechanisms involved was investigated. METHODOLOGY/PRINCIPAL FINDINGS: Bmv (1 µg) was injected through the intraplantar route in the right hind paw of mice. Mechanical hyperalgesia and allodynia were evaluated by von Frey filaments at different time points after venom injection. Low level laser therapy (LLLT) was applied at the site of Bmv injection at wavelength of red 685 nm with energy density of 2.2 J/cm2 at 30 min and 3 h after venom inoculation. Neuronal activation in the dorsal horn spinal cord was determined by immunohistochemistry of Fos protein and the mRNA expression of IL-6, TNF-α, IL-10, B1 and B2 kinin receptors were evaluated by Real time-PCR 6 h after venom injection. Photobiomodulation reversed Bmv-induced mechanical hyperalgesia and allodynia and decreased Fos expression, induced by Bmv as well as the mRNA levels of IL-6, TNF-α and B1 and B2 kinin receptors. Finally, an increase on IL-10, was observed following LLLT. CONCLUSION/SIGNIFICANCE: These data demonstrate that LLLT interferes with mechanisms involved in nociception and hyperalgesia and modulates Bmv-induced nociceptive signal. The use of photobiomodulation in reducing local pain induced by Bothropic venoms should be considered as a novel therapeutic tool for the treatment of local symptoms induced after bothropic snakebites.
Assuntos
Analgésicos/efeitos adversos , Citocinas/metabolismo , Hiperalgesia/terapia , Cininas/metabolismo , Terapia com Luz de Baixa Intensidade , Neurônios/efeitos dos fármacos , Mordeduras de Serpentes/terapia , Venenos de Serpentes/efeitos adversos , Analgésicos/administração & dosagem , Animais , Bothrops , Citocinas/genética , Feminino , Humanos , Hiperalgesia/etiologia , Hiperalgesia/genética , Hiperalgesia/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Cininas/genética , Masculino , Camundongos , Mordeduras de Serpentes/etiologia , Mordeduras de Serpentes/genética , Mordeduras de Serpentes/metabolismo , Venenos de Serpentes/administração & dosagem , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Different chemotherapy drugs are generally introduced in clinical practices combining with therapy for glioma treatment. However, these chemotherapy drugs have rarely been compared with each other and the optimum drug still remains to be proved. In this research, medical databases were consulted, PubMed, Embase and Cochrane Library included. As primary outcomes, hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with their corresponding 95% credential intervals (CrI) were reported. A network meta-analysis was conducted; the surface under the cumulative ranking curve (SUCRA) was utilized for treatment rank and a cluster analysis based on SUCRA values was performed. This research includes 14 trials with 3,681 subjects and eight interventions. In terms of network meta-analysis, placebo was proved to be inferior to the combination of temozolomide (TMZ), nimustine (ACNU) and cisplatin (CDDP). Also, bevacizumab (BEV) in conjunction with TMZ were significantly more effective than placebo with an HR of 0.40. The estimated probabilities from SUCRA verified the above outcomes, confirming that the combination of TMZ, ACNU and CDDP exhibited the highest ranking probability of 0.889 with respect to OS, while BEV in combination with TMZ - with a probability of 0.772 - ranked the first place with respect to PFS. According to the results of this network meta-analysis, the combination of (1) TMZ, ACNU and CDDP; (2) BEV in combination with TMZ and (3) cilengitide in combination with TMZ, are considered as the preferable choices of chemotherapy drugs for glioma treatment.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Glioma/terapia , Anticorpos Monoclonais Humanizados , Antineoplásicos/administração & dosagem , Teorema de Bayes , Bevacizumab/administração & dosagem , Neoplasias Encefálicas/mortalidade , Cisplatino/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Intervalo Livre de Doença , Eflornitina/administração & dosagem , Glioma/mortalidade , Humanos , Mitolactol/administração & dosagem , Metanálise em Rede , Nimustina/administração & dosagem , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Venenos de Serpentes/administração & dosagem , Temozolomida , Resultado do Tratamento , Vincristina/administração & dosagemRESUMO
Protein therapy has been considered the most direct and safe approach to treat cancer. Targeting delivery of extracellularly active protein without internalization barriers, such as membrane permeation and endosome escape, is efficient and holds vast promise for anticancer treatment. Herein, we describe a "transformable" core-shell based nanocarrier (designated CS-NG), which can enzymatically assemble into microsized extracellular depots at the tumor site with assistance of hyaluronidase (HAase), an overexpressed enzyme at the tumor microenvironment. Equipped with an acid-degradable modality, the resulting CS-NG can substantially release combinational anticancer drugs-tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and antiangiogenic cilengitide toward the membrane of cancer cells and endothelial cells at the acidic tumor microenvironment, respectively. Enhanced cytotoxicity on MDA-MB-231 cells and improved antitumor efficacy were observed using CS-NG, which was attributed to the inhibition of cellular internalization and prolonged retention time in vivo.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Venenos de Serpentes/administração & dosagem , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Endossomos/efeitos dos fármacos , Humanos , Hialuronoglucosaminidase/biossíntese , Hialuronoglucosaminidase/química , Camundongos , Venenos de Serpentes/química , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Malignant gliomas especially glioblastoma (GBM) are poorly responsive to the current treatments. Cilengitide (CGT) is a cyclic pentapeptide that demonstrated efficacy for GBM treatment by targeting the integrins avß3 and avß5 over-expressed on GBM cells. However, clinical translation of this therapy has been limited by issues including fast blood clearance, high kidney and liver uptake, poor blood-brain barrier (BBB) penetration, low tumor specificity and rapid washout from tumors. In this study, these issues were tackled in an integrated manner using a multi-stage strategy combining ultrasound-targeted microbubble destruction (UTMD) with CGT nanotherapy. CGT nanoparticles (CGT-NP) prepared using gelatin and Poloxamer 188-grafted heparin copolymer demonstrated significant apoptotic and cytotoxic effects in C6 GBM cells. Biodistribution study in a rat GBM model demonstrated buildup of high CGT level in tumors subjected to CGT-NP+UTMD combined therapy. The tumor CGT level in these animals was increased over 3-fold, tumor retention of CGT prolonged and renal clearance significantly reduced when compared with free CGT with or without UTMD. CGT-NP+UTMD treatment was further shown to extend the median survival period from less than 20days in the control and about 30days in free CGT group to about 80days. This was achieved with low CGT dosing level (2mg/kg twice weekly). In situ monitoring of GFAP, Ki67, caspase-3, Beclin-1, and LC-3 in the tumor samples together with TUNEL assay, transmission electron microscope imaging and Western blot assay all demonstrated high apoptotic and autophagy activities induced by the combined therapy. In conclusion, this study has provided extensive preclinical data supporting the use of this combined therapy to overcome the limitations of standard CGT treatment of gliomas.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Venenos de Serpentes/administração & dosagem , Venenos de Serpentes/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Heparina/química , Masculino , Microbolhas , Nanopartículas , Proteínas de Neoplasias/metabolismo , Poloxâmero , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , Distribuição Tecidual , UltrassomRESUMO
Neurotoxic envenomation following bites by kraits (Bungarus species) is a leading cause of snakebite mortality in South Asia. Over a long time, this had been attributed only to one species, the common krait (Bungarus caeruleus). However, recent research has provided increasing evidence of the involvement of several krait species. Here, we report a fatal case of neurotoxic envenomation following the bite of a greater black krait (Bungarus niger) in Nepal. Case presentation A 33-year-old man was bitten in the outdoor corridor of his home in the eastern hills of Ilam district while handling a snake he thought to be non-venomous. He subsequently developed severe abdominal pain, frequent vomiting, and signs of neurotoxic envenomation leading to respiratory paralysis. The patient did not respond to Indian polyvalent antivenom given 4 h after the bite and died under treatment 8 h after the bite. This is the second time that a B. niger was observed in Nepal, the first documented case of envenomation by this species in the country and the sixth reported case worldwide. Conclusions Previous distribution records from eastern India and western Nepal, from western hills in Nepal, and from lowland localities in India and Bangladesh indicate risk of envenomation by B. niger throughout the low and intermediate elevations of Nepal up to at least 1,500 m above sea level. As very few people in Nepal bring killed snakes to healthcare centers and because there is a general belief among local people that there are no kraits in the hills, bites by B. niger are likely to be misdiagnosed and underreported.
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Animais , Venenos de Serpentes/administração & dosagem , Venenos de Serpentes/análise , Venenos de Serpentes/química , Venenos de Serpentes/toxicidade , Agentes Neurotóxicos/análise , Agentes Neurotóxicos/intoxicação , SerpentesAssuntos
Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Hipóxia Celular , Humanos , Recidiva Local de Neoplasia/irrigação sanguínea , Venenos de Serpentes/administração & dosagem , Venenos de Serpentes/uso terapêuticoRESUMO
PURPOSE: Fit-for-purpose pharmacodynamic biomarkers could expedite development of combination antiangiogenic regimens. Plasma sVEGFR2 concentrations ([sVEGFR2]) mark sunitinib effects on the systemic vasculature. We hypothesized that cilengitide would impair microvasculature recovery during sunitinib withdrawal and could be detected through changes in [sVEGFR2]. EXPERIMENTAL DESIGN: Advanced solid tumor patients received 50 mg sunitinib daily for 14 days. For the next 14 days, patients were randomized to arm A (cilengitide 2,000 mg administered intravenously twice weekly) or arm B (no treatment). The primary endpoint was change in [sVEGFR2] between days 14 and 28. A candidate pharmacodynamic biomarker of cilengitide inhibition of integrin αvß3, serum c-telopeptide collagen crosslinks (CTx), was also measured. RESULTS: Of 21 patients, 14 (7 per arm) received all treatments without interruption and had all blood samples available for analysis. The mean change and SD of [sVEGFR2] for all sunitinib-treated patients was consistent with previous data. There was no significant difference in the mean change in [sVEGFR2] from days 14 to 28 between the arms [arm A: 2.8 ng/mL; 95% confidence interval (CI), 2.1-3.6 vs. arm B: 2.0 ng/mL; 95% CI, 0.72-3.4; P = 0.22, 2-sample t test]. Additional analyses suggested (i) prior bevacizumab therapy to be associated with unusually low baseline [sVEGFR2] and (ii) sunitinib causes measurable changes in CTx. CONCLUSIONS: Cilengitide had no measurable effects on any circulating biomarkers. Sunitinib caused measurable declines in serum CTx. The properties of [sVEGFR2] and CTx observed in this study inform the design of future combination antiangiogenic therapy trials.
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Biomarcadores Tumorais/sangue , Colágeno Tipo I/sangue , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Peptídeos/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Biomarcadores Tumorais/farmacocinética , Colágeno Tipo I/farmacocinética , Feminino , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/sangue , Neoplasias/genética , Neoplasias/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Peptídeos/farmacocinética , Pirróis/administração & dosagem , Pirróis/farmacocinética , Venenos de Serpentes/administração & dosagem , Venenos de Serpentes/farmacocinética , Sunitinibe , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. RESULTS: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvß3 and αvß5 expression was neither a predictive nor a prognostic indicator. CONCLUSIONS: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT00842712.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Cetuximab/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Receptores ErbB/metabolismo , Feminino , Humanos , Integrina alfaVbeta3/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Receptores de Vitronectina/metabolismo , Venenos de Serpentes/administração & dosagem , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , GencitabinaRESUMO
BACKGROUND: Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with cilengitide, an integrin inhibitor. METHODS: This phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent glioblastoma. Once the maximum tolerated dose was determined, 40 patients enrolled in a dose expansion cohort with 20 being exposed to anti-VEGF therapy and 20 being naive. The primary endpoint was safety. Secondary endpoints included overall survival, proportion of participants alive and progression free at 6 months, radiographic response, and exploratory analyses of physiological imaging and blood biomarkers. RESULTS: Forty-five patients enrolled, and no dose toxicities were observed at a dose of cediranib 30 mg daily and cilengitide 2000 mg twice weekly. Complete response was seen in 2 participants, partial response in 2, stable disease in 13, and progression in 21; 7 participants were not evaluable. Median overall survival was 6.5 months, median progression-free survival was 1.9 months, and progression-free survival at 6 months was 4.4%. Plasma-soluble VEGFR2 decreased with treatment and placental growth factor, carbonic anhydrase IX, and SDF1α, and cerebral blood flow increased. CONCLUSIONS: The combination of cediranib with cilengitide was well tolerated and associated with changes in pharmacodynamic blood and imaging biomarkers. However, the survival and response rates do not warrant further development of this combination.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Quinazolinas/uso terapêutico , Venenos de Serpentes/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/patologia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Venenos de Serpentes/administração & dosagem , Venenos de Serpentes/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/PURPOSE: Mainstream models for anal sphincter injury use large animals. We developed a simple and stable anal sphincter injury model in a small animal (i.e., rats) to obtain manometry measurements by using a miniaturized probe and applying cardiotoxin. METHODS: The histological structure of the anal canal was evaluated by using manometry in normal rats (n=40). We damaged the internal and external anal sphincters by locally administering snake poison (cardiotoxin; 20 uM, 100µL 8 points). We evaluated the anal canal function through manometry measurements (n=5) and examined the histology using hematoxylin-eosin staining (at each time point, n=3; total n=15). RESULTS: The manometry parameters and structure of the anal canal of normal rats were similar to those of humans, because rats have resting pressure, rectoanal reflex in the manometry, and an external and internal anal sphincter. After inducing injury, the following findings were observed: rhythmic wave loss and a remarkable reduction in the anal sphincter resting pressure; and local bleeding and advanced infiltration of the inflammatory cells (day 1) and the loss of muscle fibers (day 3). CONCLUSION: This new rat model will contribute to increasing the knowledge on the anal canal.
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Canal Anal/lesões , Cardiotoxinas/toxicidade , Modelos Animais , Ratos Sprague-Dawley/lesões , Venenos de Serpentes/toxicidade , Canal Anal/efeitos dos fármacos , Canal Anal/patologia , Canal Anal/fisiopatologia , Animais , Cardiotoxinas/administração & dosagem , Feminino , Manometria , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley/fisiologia , Venenos de Serpentes/administração & dosagemRESUMO
Cilengitide (EMD 121974, manufactured by Merck KGaA, Darmstadt, Germany) is an αv-integrin receptor antagonist showing high affinity for αvß3 and αvß5.This study determined the mass balance of cilengitide in healthy volunteers receiving a single intravenous infusion of 2.1 MBq (14) C-cilengitide spiked into 250 mL of 2000 mg of cilengitide. Blood, urine, and feces were collected up to day 15 or until excretion of radioactivity was below 1% of the administered dose. Total radioactivity derived from the administration of (14) C-cilengitide and unlabeled cilengitide levels were determined and used for calculation of pharmacokinetic parameters.(14) C-cilengitide-related radioactivity was completely recovered (94.5%; 87.4%-100.6%) and was mainly excreted into urine (mean, 79.0%; range, 70.3%-88.2%) and to a lesser extent into feces (mean, 15.5%; range, 9.3%-20.3%). Of the administered dose, 77.5% was recovered as unchanged cilengitide in urine. The concentration profiles of cilengitide and total radioactivity in plasma were comparable. No circulating metabolites were identified in plasma and urine. Two metabolites,M606-1 and M606-2, were identified in feces considered to be formed by intestinal peptidases or by peptidases from fecal bacteria. In conclusion, the data show that following intravenous administration, (14) C-cilengitide was completely recovered, was excreted mainly via renal elimination, and was not metabolized systemically.