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1.
In Vivo ; 28(1): 75-80, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24425839

RESUMO

AIM: To propose an innovative methodology for the monitoring of the evolution of induced subcutaneous tumors in mice. MATERIALS AND METHODS: A new 3D scanner able to measure the tumor mass volume is presented. The scanner is based on the projection of a fringe pattern onto the sample surface (structured light). The lines are diffused by the sample and then collected by a digital camera. The obtained 2D-image is treated by the scanner's software that extracts the 3D information and evaluates the sample volume. RESULTS: The 3D scanner has been successfully used in the measurement of subcutaneous HT-29 colorectal cancer xenografts treated with 5-fluorouracil, bevacizumab and their combination. Comparison with simple caliper measurements revealed important and significant differences between the two measurement techniques. CONCLUSION: The proposed methodology is more effective than the usual approach based on caliper measurements.


Assuntos
Neoplasias Colorretais/diagnóstico , Imageamento Tridimensional , Software , Animais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Fluoruracila/administração & dosagem , Células HT29 , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Target Oncol ; 9(3): 205-14, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23821377

RESUMO

This study was conducted to describe the modulation of plasma epidermal growth factor receptor (EGFR) ligands in EGFR-positive metastatic colorectal cancer (mCRC) patients during treatment with cetuximab and irinotecan and to explore the clinical implication of plasma levels' variations as potential biomarkers of benefit. Plasma amphiregulin (AR), epidermal growth factor (EGF), transforming growth factor-α, and heparin binding-EGF were assessed by ELISA in 45 chemorefractory mCRC patients, treated with cetuximab and irinotecan. Plasma levels were measured before and 1 h after the first administration of cetuximab, before and 1 h after the second administration, and before the third and the fifth cycles. KRAS and BRAF mutational status were determined. EGFR ligands' levels were differently modulated according to tumor KRAS and BRAF mutational status. In KRAS wild-type patients (n = 34), AR and EGF early increased and higher increases were significantly associated with worse clinical outcome. By adopting a specific cut-off value, patients with higher levels of AR 1 h after the first administration had significantly worse response rate, progression free survival, and overall survival. This hypothesis-generating study shows that EGFR ligands are significantly modulated by cetuximab plus irinotecan according to KRAS and BRAF mutational status, and they warrant further investigation as pharmacodynamic markers of resistance to anti-EGFRs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Irinotecano , Ligantes , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
3.
J Clin Endocrinol Metab ; 98(9): E1465-73, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23969186

RESUMO

CONTEXT: Recent experimental evidence suggests a rationale for the use of multitarget tyrosine kinase inhibitors for the treatment of thyroid cancers. Sunitinib showed promising preliminary results against anaplastic thyroid cancer (ATC), and it has been used for some patients who are ineligible for clinical trials. OBJECTIVES: The aims of this study were to investigate the in vitro and in vivo activity of sunitinib on ATC and on microvascular endothelial cells and the molecular mechanism for the observed sunitinib activity. METHODS: Proliferation and apoptotic assays were performed on human dermal microvascular endothelial and on BRAF- or H-ras-mutated ATC cells (8305C and FB3, respectively) after in vitro exposure to sunitinib for 72 hours. Vascular endothelial growth factor receptor-2, epithelial growth factor receptor, ERK1/2, and Akt phosphorylation was quantified by ELISA and Western blot. Cyclin-D1 mRNA expression was evaluated by real-time PCR, and cyclin-D1 intracellular concentrations were measured by ELISA. 8305C tumor xenografts in nude mice were treated with sunitinib at 50 mg/kg/d (i.p.). RESULTS: Antiproliferative and proapoptotic activity of sunitinib was observed in both endothelial and ATC cells. Phospho-vascular endothelial growth factor receptor-2 levels significantly decreased after sunitinib treatment in activated endothelial cells. Phospho-epidermal growth factor receptor, ERK1/2, and Akt phosphorylation was significantly inhibited by sunitinib treatment in endothelial and cancer cells, and cyclin-D1 mRNA and protein expression was inhibited. Sunitinib administration in vivo caused significant inhibition of tumor growth (P < .05). CONCLUSIONS: Sunitinib is active in vitro and in vivo against activated endothelial and ATC cells via the inhibition of Akt and ERK1/2 phosphorylation and through the down-regulation of cyclin-D1.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Células Endoteliais/efeitos dos fármacos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Receptores ErbB/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Fosforilação/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Sunitinibe , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
4.
ScientificWorldJournal ; 2012: 420190, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22919317

RESUMO

In this prospective, case-control genetic study, 120 consecutive neovascular age-related macular degeneration (AMD) cases and 78 controls were enrolled. Two SNPs (rs2071559 and rs1870377) of VEGF-A receptor-2 (VEGFR-2) gene were analyzed with the technique of Real-Time PCR to investigate a genetic link between AMD and VEGFR-2 gene polymorphisms in Italian patients. The frequency of the VEGFR-2 genotype rs2071559 AA was significantly lower (18.33%) in patients with AMD than in the control subjects (34.62%; P = 0.0095, chi-square test; P(corr) = 0.038; OR = 0.42, 95% CI 0.22 to 0.82). In conclusion, although with the limitations of a small sample size and the few SNPs studied, this study demonstrates a lower frequency of VEGFR-2 rs2071559 AA genotype in an AMD patient population, suggesting future studies on the role VEGFR-2 SNPs.


Assuntos
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Degeneração Macular Exsudativa/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real
5.
Angiogenesis ; 15(2): 275-86, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22382585

RESUMO

AIMS: To evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies. METHODS: Thirty-eight patients received 500 mg/mq(2) CTX i.v bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 100 mg/twice a day UFT p.o. and 200 mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH(2), GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed. RESULTS: Seventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8 ms (range, 4.2-7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7 ms (95% CI, 1.6-3.9 ms) and 7.1 ms (95% CI, 4.3-9.9 ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and C(max) values greater than 1.313 h × µg/ml and 0.501 µg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients. CONCLUSION: Metronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclofosfamida/farmacocinética , Neoplasias Gastrointestinais/tratamento farmacológico , Pirazóis/farmacocinética , Sulfonamidas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Celecoxib , Ciclofosfamida/administração & dosagem , Feminino , Neoplasias Gastrointestinais/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Tegafur/administração & dosagem , Tegafur/farmacocinética , Uracila/administração & dosagem , Uracila/farmacocinética , Fator A de Crescimento do Endotélio Vascular/sangue
7.
Biochem Pharmacol ; 81(11): 1309-16, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21459081

RESUMO

AIMS: To demonstrate the antiproliferative and pro-apoptotic activity of the novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone and in combination with SN-38 (the active metabolite of irinotecan), on endothelial and tumor cells and to show its mechanism of action. METHODS: Proliferation and apoptotic assays were performed on microvascular endothelial (HMVEC-d) and lung (A549) and thyroid cancer (8305C, TT) cell lines exposed to CLM3 and to the simultaneous combination with SN38 for 72h. Cell-based phospho-VEGFR-2, phospho-EGFR and phospho-RET inhibition assays were performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Cyclin D1 gene expression was performed with real-time PCR and cyclin D1 intracellular concentrations were measured by ELISA. RESULTS: A strong effect on antiproliferative and pro-apoptotic activity was found with the CLM3 on endothelial and cancer cells, synergistically enhanced by SN38. Phospho-VEGFR-2, phospho-EGFR and phospho-RET levels significantly decreased after CLM3 treatments in activated endothelial and cancer cells; ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the pyrazolopyrimidine drug in endothelial cells if compared to cancer cells. Moreover, CLM3 treatment greatly inhibited the expression of the cyclin D1 gene in endothelial and cancer cells, decreasing the cyclin D1 protein intracellular concentration. CONCLUSIONS: The pyrazolopyrimidine derivative CLM3 demonstrated a highly significant and promising antiproliferative and proapoptotic activity, alone and in combination with SN-38, for activated endothelial and cancer cells. These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signaling pathways.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Endotélio Vascular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Linhagem Celular Tumoral , Ciclina D1/genética , Quimioterapia Combinada , Endotélio Vascular/citologia , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Irinotecano , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem
8.
Neoplasia ; 13(3): 217-29, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21390185

RESUMO

AIMS: To demonstrate the synergistic antiproliferative and proapoptotic activity of irinotecan and axitinib in vitro and the improvement of the in vivo effects on angiogenesis and pancreatic cancer. METHODS: Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells and pancreas cancer (MIAPaCa-2, Capan-1) cell lines exposed to SN-38, the active metabolite of irinotecan, axitinib, or their simultaneous combination for 72 hours. ERK1/2 and Akt phosphorylation, the vascular endothelial growth factor (VEGF), VEGF receptor-2, and thrombospondin-1 (TSP-1) concentration were measured by ELISAs. ATP7A and ABCG2 gene expression was performed with real-time polymerase chain reaction and SN-38 intracellular concentrations were measured by high-performance liquid chromatography. Capan-1 xenografts in nude mice were treated with irinotecan and axitinib alone or in simultaneous combination. RESULTS: A strong synergistic effect on antiproliferative and proapoptotic activity was found with the axitinib/SN-38 combination on endothelial and cancer cells. ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the combined drugs in all the cell lines. Axitinib and SN-38 combined treatment greatly inhibited the expression of the ATP7A and ABCG2 genes in endothelial and cancer cells, increasing the SN-38 intracellular concentration. Moreover, TSP-1 secretion was increased in cells treated with both drugs, whereas VEGFR-2 levels significantly decreased. In vivo administration of the simultaneous combination determined an almost complete regression of tumors and tumor neovascularization. CONCLUSIONS: In vitro results show the highly synergistic properties of simultaneous combination of irinotecan and axitinib on endothelial and pancreas cancer cells, suggesting a possible translation of this schedule into the clinics.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/prevenção & controle , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Animais , Axitinibe , Western Blotting , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Células Cultivadas , ATPases Transportadoras de Cobre , Sinergismo Farmacológico , Endotélio Vascular/citologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imidazóis/administração & dosagem , Técnicas Imunoenzimáticas , Indazóis/administração & dosagem , Irinotecano , Masculino , Camundongos , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica , Neoplasias Pancreáticas/irrigação sanguínea , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trombospondinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Eur J Pharmacol ; 619(1-3): 8-14, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19695243

RESUMO

Metronomic chemotherapy (the frequent, long term, low dose administration of chemotherapeutic drugs) is a promising therapy because it enhances the anti-endothelial activity of conventional chemotherapeutics, but with lower or no toxic effects compared to maximum tolerated dose administration. The aims of the present study were to compare, in vitro and in vivo, the antiangiogenic and antitumor activities of metronomic irinotecan (CPT-11), oxaliplatin (L-OHP) and 5-fluorouracil (5-FU) in colorectal cancer and to investigate the metronomic combination of these drugs. In vitro cell proliferation, combination studies and vascular endothelial growth factor (VEGF) secretion analyses were performed on endothelial (HMVEC-d) and colorectal cancer (HT-29) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11, L-OHP and 5-FU. HT-29 human colorectal cancer xenograft model was used and tumour growth, microvessel density and VEGF quantification were performed in tumours after the administration of metronomic CPT-11, L-OHP, 5-FU and their simultaneous combination. Low concentrations of SN-38, but not 5-FU and L-OHP, preferentially inhibited endothelial cell proliferation. Simultaneous and continuous exposure of HT-29 and HMVEC-d cells to low concentrations SN-38+L-OHP+5-FU for 144 h showed a strong antagonism and an unfavorable dose-reduction index. Moreover, the ternary combination resulted in a significant increase of VEGF secretion in HT-29 cancer cells. In a xenograft model metronomic CPT-11, but not 5-FU and L-OHP, significantly inhibits HT-29 tumor growth and microvessel density in the absence of toxicity. On the contrary, metronomic 5-FU+L-OHP+CPT-11 therapy did not affect the microvascular count. The metronomic concept might not universally apply to every cytotoxic drug in colorectal cancer and metronomic combination regimens should be used with caution.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Esquema de Medicação , Células Endoteliais/citologia , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Irinotecano , Masculino , Camundongos , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Neovascularização Patológica/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Fator A de Crescimento do Endotélio Vascular/metabolismo
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