Bevacizumab Reduces VEGF Expression in Patients with Relapsed and/or Refractory Acute Myeloid Leukaemia (AML) without Clinical Antileukemic Activity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4543-4543
Author(s):  
Lejla Zahiragic ◽  
Christoph Schliemann ◽  
Ralf Bieker ◽  
Wolfgang E. Berdel ◽  
Rolf M. Mesters
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Wilcoxon Test ◽  
Vascular Endothelial ◽  
Antileukemic Activity ◽  
Vegf Expression ◽  
Wide Range ◽  
Endothelial Growth Factor ◽  
Refractory Aml

Abstract Angiogenesis is required for tumor growth and metastasis and is an attractive target for cancer therapy. Because of its pivotal role in tumorassociated angiogenesis across a wide range of malignancies, vascular endothelial growth factor-A (VEGF-A) has emerged as a central therapeutic target in cancer. Neoangiogenesis has been shown to play an important role in the pathogenesis of AML (Padro et al., Blood 2000) and antiangiogenic therapy could constitute a novel strategy for its treatment (Mesters et al., Blood 2001). Autocrine and paracrine secretion of vascular endothelial growth factor (VEGF) in the bone marrow may promote proliferation and survival of leukemic blasts (Fiedler et al., Blood 1997). This concept represented the rationale for the therapeutic application of bevacizumab (BV), a recombinant humanised monoclonal antibody against VEGF, in patients with advanced AML after failure of standard treatment. Nine patients (median age 63 years; range 46–81 years) with relapsed and/or refractory AML not judged medically fit for further intensive chemotherapy were enrolled in this study. All patients received at least one cycle of BV (10 mg/kg body weight), 5 patients received 2 cycles (days 1 and 14) and 2 patients a 3rd cycle (day 35). Treatment was well tolerated, without treatment-related side effects. Two patients had to be withdrawn from drug administration after cycle one due to progressive disease. After treatment with BV none of the patients fulfilled the criteria of a partial response, defined as the clearance of at least 50 % marrow blasts accompanied by increases in platelet counts and haemoglobin values. The level of VEGF expression in the bone marrow determined by immunohistochemistry significantly decreased during treatment with BV (before BV treatment: median of 3.78 arbitrary units (AU) [range 1.5–5.8 AU]; after BV treatment: median of 2.57 AU [range 1.3–5.0 AU]; Wilcoxon test, P<0.05). In contrast, VEGFR-2 expression by leukemic blasts and bone marrow microvessel density did not change significantly. In conclusion, single agent BV has no significant antileukemic activity in relapsed and/or refractory AML.

Increased expression of vascular endothelial growth factor receptor 1 correlates with VEGF and microvessel density in Philadelphia chromosome-negative myeloproliferative neoplasms

2011 ◽  
Vol 64 (3) ◽  
pp. 226-231 ◽  
Author(s):  
Leonardo Boiocchi ◽  
Claudia Vener ◽  
Federica Savi ◽  
Emanuela Bonoldi ◽  
Alessia Moro ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Microvessel Density ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

AimsThe authors investigated vascular endothelial growth factor receptor 1 (VEGFR-1) protein expression in a series of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph- MPNs) and its correlations with microvessel density (MVD) and vascular endothelial growth factor (VEGF).Methods83 bone marrow biopsies of Ph- MPNs patients, including 27 essential thrombocythaemia (ET), 21 polycythaemia vera (PV) and 35 primary myelofibrosis (PMF), and 10 normal controls (NCs) were investigated by immunohistochemistry.ResultsPatients with PV and PMF showed an increased MVD (PV: 20.1±10.6; PMF: 25.8±6.5) compared with those with ET or NCs (ET: 10.4±4.6; NCs: 7±3.4). VEGFR-1 expression was increased in Ph- MPNs, particularly in PV and PMF (NCs: 0.07±0.03; ET: 0.15±0.09; PV: 0.31±0.2; PMF: 0.31±0.04). VEGF expression parallelled VEGFR-1 and resulted increased in Ph- MPNs (NCs: 0.08±0.04; ET: 0.13±0.06; PV: 0.29±0.2; PMF: 0.31±0.15) and higher in post-polycythaemic myelofibrosis and in the fibrotic stage of PMF than in the non-fibrotic phases of both diseases. VEGFR-1 protein expression correlated with MVD and VEGF expression in Ph- MPNs. VEGFR-1 and VEGF were expressed by the same bone marrow populations: megakaryocytes, macrophages and immature myeloid precursors showed a moderate to strong immunostaining intensity in both Ph- MPNs and NCs. The erythroid precursors were not immunoreactive.ConclusionsVEGFR-1 and VEGF were increased and co-localised in megakaryocytes, macrophages and myeloid precursors of Ph- MPNs. This finding supports the hypothesis of a VEGF/VEGFR-1 autocrine loop in the neoplastic cells of Ph- MPNs.

Vascular Endothelial Growth Factor (VEGF) Acts Via Auto- and Paracrine Mechanisms as a Critical Microenvironmental Factor for the Survival of Chronic Lymphocytic Leukemia (CLL) Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4376-4376
Author(s):  
Iris Gehrke ◽  
Julian Paesler ◽  
Rajesh Kumar Gandhirajan ◽  
Regina Razavi ◽  
Simon Jonas Poll-Wolbeck ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Endothelial Growth Factor ◽  
B Cells ◽  
Growth Factor ◽  
Feedback Loop ◽  
Stromal Cell ◽  
Lymphocytic Leukemia ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Abstract Abstract 4376 The major pathophysiological characteristic of chronic lymphocytic leukemia (CLL) is the accumulation of malignant, immuno-incomptetent B-cells, which is commonly known as the apoptotic block. Recently, it was speculated that vascular endothelial growth factor (VEGF) might be involved in this process. Whereas most of the available studies are solely descriptive, functional data are largely missing. The aim of this study was therefore to describe the effect and functional background of VEGF on CLL cells for the identification of potential strategies for a targeted CLL therapy. We identified an autocrine VEGF feedback loop in CLL cells, but not healthy B-cells. Recombinant human (rh) VEGF stimulation lead to increased expression of the anti-apoptotic proteins Mcl1 and XIAP, but was not sufficient to prolong survival. When CLL cells were cocultured with the bone marrow derived stromal cell line HS5, survival was significantly enhanced 28.5 ± 6.5% after 72h relative to monoculture, whereas healthy B-cells did not profit from coculture (-0.5 ± 4.7%). HS5 cells produce and secrete high amounts of VEGF themselves. When cocultured with HS5 CLL cells also showed an increased VEGF expression, indicating the existence of a paracrine VEGF feedback loop. The actual relevance of VEGF in the coculture mediated survival support was proofed by siRNA experiments. When VEGF expression and secretion was downregulated in HS5 cell by siRNA, the survival advantage CLL cells obtained from the coculture was reduced down to that in monoculture. Also the addition of a VEGF-neutralizing monoclonal antibody largely reversed the survival supporting effect of the coculture, clearly indicating the critical role of VEGF in bone marrow stromal cell-mediated CLL cell survival. We further found rhVEGF to induce upregulation and activation of STAT3 via Tyr705-phosphorylation and a subsequent expression of STAT3 targets such as Cyclin D1 and BclXL. VEGF-stimulation further induced downregulation of the tumor suppressor RB1 and E2F1, which act as proapoptotic factors. Vice versa inhibition of VEGF by using selective VEGF-R inhibitors reduced both, Tyr705 phosphorylation and expression of STAT3 target genes. We therefore, propose a dual mechanism of VEGF-mediated CLL cell survival support via upregulation of the potent oncogene STAT3 and downregulation of the tumor suppressor RB1/E2F1. Hence, VEGF might function as a potential new therapeutic target to overcome the apoptotic block in CLL cells. Disclosures: Hallek: BayerScheringAG: Honoraria, Research Funding.

scholarly journals Effect of directly acting anti-viral agents on immunological imprints in chronic HCV-4a patients: interleukin-10 and vascular endothelial growth factor genes expression level

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Iman S. Naga ◽  
Amel Abdel Fattah Kamel ◽  
Said Ahmed Ooda ◽  
Hadeer Muhammad Fath Elbab ◽  
Rania Mohamed El-Sharkawy
Keyword(s):  
Gene Expression ◽  
Vascular Endothelial Growth Factor ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Factor ◽  
Angiogenic Factor ◽  
Vascular Endothelial ◽  
Wide Range ◽  
Chronic Hcv ◽  
Endothelial Growth Factor

Abstract Background Hepatitis C virus infection is a global health challenge with Egypt being one of the highly affected countries. IL-10 has been suggested as a suitable marker to assess necroinflammation and to monitor the progression of liver damage. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor playing a central role in many physiological as well as pathological processes. Several factors can be predictive of the response to treatment and achievement of SVR; some of which are host-related, and others are virus-related. The gene expression of IL-10 and VEGF have multiple effects for treatment response. The aim of the present work was to study the effect of treatment with directly acting agents (DAA) on the expression of VEGF and IL-10 genes in chronic hepatitis C virus-infected Egyptian genotype-4a patients. Twenty-five HCV subjects where evaluated for IL-10 and VEGF gene expression before and after treatment with DAA. Results IL-10 expression was downregulated in 92% of the cases. VEGF expression was heterogeneous showing spreading of values along a wide range with 64% of the cases being downregulated. Conclusion DAAs do not completely reverse the immunological imprints established upon chronic HCV infection.

Vascular Endothelial Growth Factor (VEGF) Expression in Healthy and Inflamed Human Dental Pulps

2002 ◽  
Vol 28 (1) ◽  
pp. 20-23 ◽  
Author(s):  
L ARTESE ◽  
C RUBINI ◽  
G FERRERO ◽  
M FIORONI ◽  
A SANTINELLI ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

scholarly journals Vascular Endothelial Growth Factor (VEGF) Expression in Human Coronary Atherosclerotic Lesions

Circulation ◽  
1998 ◽  
Vol 98 (20) ◽  
pp. 2108-2116 ◽  
Author(s):  
Mayumi Inoue ◽  
Hiroshi Itoh ◽  
Makiko Ueda ◽  
Takahiko Naruko ◽  
Akiko Kojima ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Atherosclerotic Lesions ◽  
Endothelial Growth Factor

scholarly journals The Involvement of Angiotensin Type 1 and Type 2 Receptors in Estrogen-Induced Cell Proliferation and Vascular Endothelial Growth Factor Expression in the Rat Anterior Pituitary

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Hanna Lawnicka ◽  
Dorota Ptasinska-Wnuk ◽  
Slawomir Mucha ◽  
Jolanta Kunert-Radek ◽  
Marek Pawlikowski ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Blood Vessels ◽  
Proliferation Index ◽  
Pituitary Cells ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Rat Pituitary ◽  
Endothelial Growth Factor

The aim of our study was to examine the involvement of renin-angiotensin system (RAS) in estrogen-induced lactotropes proliferation and vascular endothelial growth factor (VEGF) expression in rat pituitary. The study was performed on Fisher 344 rats underwent 8-day treatment with diethylstilboestrol (DES). The proliferation index (PCNA) and VEGF expression in pituitary sections were estimated using immunohistochemical methods. Treatment with DES increased the number of PCNA-positive cells, VEGF-positive cells, and VEGF-positive blood vessels in pituitary. Stimulatory effect of estrogen on cell proliferation and VEGF expression in blood vessels was attenuated by losartan, PD123319, and captopril. VEGF immunoreactivity in pituitary cells of DES-treated rats was decreased by AT1 antagonist and not changed by AT2 blocker and ACE inhibitor. Our findings suggest the involvement of RAS in DES-induced cell proliferation and VEGF expression in pituitary. Both the AT1 and AT2 receptors appear to mediate the estrogen-dependent mitogenic and proangiogenic effects in rat pituitary.

scholarly journals Prognostic significance of cellular vascular endothelial growth factor (VEGF) expression in the course of chronic myeloid leukaemia

2009 ◽  
Vol 137 (7-8) ◽  
pp. 379-383 ◽  
Author(s):  
Ana Vidovic ◽  
Gradimir Jankovic ◽  
Dragica Tomin ◽  
Maja Perunicic-Jovanovic ◽  
Irena Djunic ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor ◽  
The Impact

Introduction. Increased angiogenesis in bone marrow is one of the characteristics of chronic myeloid leukaemia (CML), a clonal myeloproliferative disorder that expresses a chimeric bcr/abl protein. Vascular endothelial growth factor (VEGF) is one of the most potent and a specific regulator of angiogenesis which principally targets endothelial cells and regulates several of their functions, including mitogenesis, permeability and migration. The impact of elevated VEGF expression on the course of chronic myeloid leukaemia is unknown. Objective. The aim of this study was the follow-up of VEGF expression during the course of CML. Methods. We studied VEGF expression of 85 CML patients (median age 50 years, range 16-75 years). At the commencement of the study, 29 patients were in chronic phase (CP), 25 in an accelerated phase (AP), and 31 in the blast crisis (BC). The temporal expression (percentage positivity per 1000 analysed cells) VEGF proteins over the course of CML were studied using the immunohistochemical technique utilizing relevant monoclonal antibodies. It was correlated with the laboratory (Hb, WBC and platelet counts, and the percentage of blasts) and clinical parameters (organomegaly, duration of CP, AP, and BC) of disease progression. Results. The expression of VEGF protein was most pronounced in AP (ANOVA, p=0.033). The level of VEGF expression correlated inversely with the degree of splenomegaly (Pearson, r=-0.400, p=0.011). High expression of VEGF correlated with a shorter overall survival (log rank, p=0.042). Conclusion. Immunohistochemically confirmed significance of the expression of VEGF in dependence of the CML stage could be of clinical importance in deciding on the timing therapy. These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML.

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