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991.
Salzberg M Pless M Rochlitz C Ambrus K Scigalla P Herrmann R 《Investigational new drugs》2006,24(4):299-304
Summary Vascular endothelial growth factor (VEGF) is a potent stimulant of angiogenesis. SU5416, is a small molecule tyrosine kinase
inhibitor, and a potent inhibitor of VEGF- mediated Flk-1 receptor signaling. Intravenous agent SU5416 has shown evidence
of biological activity against a variety of tumor types. The current intravenous dosing regimen is not optimal for long-term
administration, which is needed for optimal efficacy. The aim of this study was to evaluate the safety profile and pharmacokinetics
of a Nanocrystal Colloidal DispersionTM (NCD) SU5416 formulation in humans. Patients with advanced and/or metastatic solid organ tumors were included in the trial;
various SU5416 regimens were tested for tolerability, safety and were evaluated concerning pharmacokinetics. The results of
this study indicate that induction of clearance after oral dosing of NCD SU5416 in humans occurs and is greater than following
IV administration. It has been confirmed that SU5416 is a high clearance compound, also as an oral NCD formulation. The NCD
formulation was well tolerated, but no effective drug serum levels could be achieved. These data help to understand the ADME
(Absorption, Distribution, Metabolism, Excretion) properties of indoline chemical class compounds. The lessons learned should
be applied in the development of next generation indoline anti-angiogenic and anti-tumor compounds. 相似文献
992.
Spontaneously diabetic Torii (SDT) rats are a new animal model of diabetes. To investigate the mechanisms controlling diabetic retinopathy, we examined the retinal changes in SDT rats and determined the molecular balance between pigment epithelium-derived factor (PEDF), an angiogenic inhibitor, and vascular endothelial growth factor (VEGF), a major angiogenic stimulator. The retinopathy in SDT rats was characterized by a low incidence of neovascular formation and absence of non-perfused areas, and high levels of both PEDF and VEGF. Proliferative neovascular membranes, that are similar to that in human eyes with proliferative diabetic retinopathy, were found in the eyes of some of the SDT rats at >50-weeks-of-age, Immunoreactivity for VEGF was detected in the retina of SDT rats and the level of VEGF increased with the duration of diabetes. More importantly, immunoreactivity for PEDF was also increased in the retina of diabetic SDT rats. Western blot analysis showed that the level of VEGF in the retina was increased by 2.4 fold at 20-week-old, and by 6.8 fold at >40-week-old compared to that of 10-weeks old SDT rats. The levels of PEDF in the retina at 20-week- and at >40-week-old were significantly higher than that of 10-weeks old SDT rats (20-week-old; 13.5-fold increase, > 40-week-old; 10.3-fold increase). Earlier studies showed that the level of PEDF was decreased and VEGF was increased in proliferative diabetic retinopathy in human eyes. The high levels of PEDF in the retina of SDT rats may contribute to the low incidence of neovascular formation and absence of non-perfused areas that do not match the typical diabetic retinopathy in humans. 相似文献
993.
Downregulation of vascular endothelial growth factor and integrinbeta3 by endostatin in a mouse model of retinal neovascularization 总被引:3,自引:0,他引:3
Retinal neovascularization is among the leading causes of vision impairment throughout the world. Intraocular expression of vascular endothelial growth factor (VEGF), an angiogenic protein, and integrins, a group of cell adhesion molecules, is closely correlated with neovascularization in such neovascular diseases. The purpose of this study is to determine the effect of endostatin, a potent anti-angiogenic factor, on gene expression of vascular endothelial growth factor (VEGF) and integrinbeta3 in a mouse model of oxygen-induced retinopathy. C57BL/6 mice were given intravitreous injections of 1.0 microg endostatin at P12. At P17, retinal VEGF and integrinbeta3 mRNA levels were measured by real-time quantitative PCR in the hyperoxia mice and in the endostatin-treated mice. Analysis of 12 separate experiments revealed a 3.5-fold decrease in VEGF levels between hyperoxia mice and endostatin-treated mice (p<0.01) and a 2.5-fold decrease in integrinbeta3 levels between hyperoxia mice and endostatin-treated mice (p<0.01). These data suggest that intraocular expression of VEGF and integrinbeta3 mRNA is down-regulated by endostatin, which may provide a new therapeutic approach for ocular neovascularization. 相似文献
994.
The aim of the study was to determine anatomical and growth factor profiles in patients with clinically significant macular oedema (CSMO) undergoing pars plana vitrectomy (PPV). Twenty patients with moderate nonproliferative diabetic retinopathy (NPDR) with persistent CSMO underwent PPV. Patients had baseline and postoperative clinical assessment including Ocular Coherence Tomography (OCT). Baseline vitreous and aqueous and serial postoperative aqueous samples were analysed for vascular endothelial growth factor-A (VEGF-A), pigment epithelium derived Factor (PEDF) and other factors (pg/ml) including hepatocyte growth factor, MMP 9, soluble flt-1 Receptor, and TGF beta1 by ELISA. Vitreous from patients with full thickness macular holes (8) and proliferative diabetic retinopathy (22) were collected for comparison as controls. Vitreous VEGF-A concentration in the NPDR group was 957 pg/ml compared to 239 pg/ml in the macula hole (FTMH) control (p < 0.0001) and 596 pg/ml compared to PDR (p = 0.006). The median diabetic vitreous PEDF concentration was 1.36 microg/ml (FTMH 2.6 microg/ml p = 0.05). In NPDR, it was higher (1.59 microg/ml) than PDR (1.27 microg/ml) p = 0.02. There were changes to the HGF, soluble flt-1 Receptor and TGF b1 concentrations in the NPDR compared to either PDR or the normal state. In CSMO, two OCT profiles were identified: dome-shaped macular elevation (Group 1) (n = 4) and diffuse-low elevation profile (Group 2) (n = 16) which also showed differences in the postoperative median aqueous VEGF concentrations despite macular volume decreasing for both. The results suggest that there is an up-regulation of VEGF in the vitreous of the diabetic eye with a reciprocal decrease in PEDF. The structural and molecular differences between the two OCT macular profiles may explain the varying response to PPV in patients with diffuse CSMO. 相似文献
995.
Clinicopathologic significance of hypoxia-inducible factor 1alpha overexpression in gastric carcinomas 总被引:4,自引:0,他引:4
Mizokami K Kakeji Y Oda S Irie K Yonemura T Konishi F Maehara Y 《Journal of surgical oncology》2006,94(2):149-154
BACKGROUND: Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in responses to hypoxia and expression of HIF-1alpha downstream genes leads to both an adapted metabolism and increased oxygen supply. We investigated the clinical significance of HIF-1alpha expression in gastric carcinoma. METHODS: We examined HIF-1alpha, vascular endothelial growth factor (VEGF), and insulin-like growth factor-2 (IGF-2) expression patterns immunohistochemically in 126 specimens of gastric carcinoma. CD34 antigen levels were also examined by immunohistochemistry to determine microvessel density (MVD) within tumors and correlations between HIF-1alpha expression, clinicopathological features, and survival were examined. RESULTS: HIF-1alpha expression correlated with tumor size (P<0.005), depth of invasion (P=0.018), VEGF expression (P=0.03), and intra-tumor MVD (P<0.005). IGF-2 expression was more prevalent in HIF-1alpha positive than in HIF-1alpha negative tumors and the 5-year survival rate was 58.4% for HIF-1alpha positive patients and 81.5% for HIF-1alpha negative patients (P=0.009). HIF-1alpha expression is an independent prognostic factor in gastric carcinoma (P=0.032). CONCLUSIONS: Overexpression of HIF-1alpha in gastric carcinomas may upregulate its downstream gene products leading to VEGF-mediated angiogenesis, and resulting in a poor prognosis for patients. 相似文献
996.
997.
998.
Des Guetz G Uzzan B Nicolas P Cucherat M Morere JF Benamouzig R Breau JL Perret GY 《British journal of cancer》2006,94(12):1823-1832
We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n = 957) for RFS and 18 for OS (n = 2383) and for VEGF in 17 studies, including nine studies for RFS (n = 1064) and 10 for OS (n = 1301). High MVD significantly predicted poor RFS (RR = 2.32 95% CI: 1.39-3.90; P < 0.001) and OS (RR = 1.44; 95% CI: 1.08-1.92; P = 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR = 2.84; 95% CI: 1.95-4.16) and OS (RR=1.65; 95% CI: 1.27-2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies. 相似文献
999.
Vlahovic G Rabbani ZN Herndon JE Dewhirst MW Vujaskovic Z 《British journal of cancer》2006,95(8):1013-1019
Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta. We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression. 相似文献
1000.
Vascular endothelial growth factor-C expression in bladder transitional cell cancer and its relationship to lymph node metastasis 总被引:3,自引:0,他引:3
OBJECTIVE: To elucidate the role of vascular endothelial growth factor-C (VEGF-C) in bladder transitional cell carcinoma (TCC), examining VEGF-C expression in bladder TCC tissue and the association of VEGF-C with clinicopathological features, as the expression of VEGF-C in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis, but there are few reports of VEGF-C expression in bladder TCC. PATIENTS AND METHODS: The study included 45 patients with bladder TCC; VEGF-C expression was assessed by immunohistochemistry and the association between VEGF-C expression and angiogenesis, as evaluated by microvessel density (MVD), was examined. RESULTS: There was VEGF-C expression in the cytoplasm of tumour cells, but very little in the normal transitional epithelium. VEGF-C expression was significantly associated with tumour size, pathological T stage, pathological grade, lymphatic-venous involvement and pelvic lymph node metastasis (all P < 0.05). Multivariate analysis showed that VEGF-C expression was an exclusive independent factor influencing pelvic lymph node metastasis. Moreover, the patients with high VEGF-C expression had a markedly poorer prognosis than those with no or low VEGF-C expression (P = 0.014). A multivariate analysis based on the Cox proportional hazard model showed that lymph node metastasis was only an independent prognostic factor in the multivariate analysis using the Cox regression model (P = 0.010). CONCLUSION: The present study provides evidence supporting the involvement of VEGF-C expression in the promotion of lymph node metastasis in bladder TCC. Examination of VEGF-C expression in biopsy specimens might be beneficial in predicting pelvic lymph node metastasis. 相似文献