Immunotherapy with Recombinant Xenogeneic Vascular Endothelial Growth Factor as a Vaccine Combined Low-Dose Adriamycin Induces Synergistic Antitumor Efficacy in EL4 Lymphoma Model.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4811-4811
Author(s):  
Ting Niu ◽  
Ting Liu ◽  
Yong-qian Jia ◽  
Yan-jun Wen ◽  
Ling Tian ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Apoptosis ◽  
Low Dose ◽  
Combination Group ◽  
Vascular Endothelial ◽  
Tumor Cell Apoptosis ◽  
Anti Vegf ◽  
Endothelial Growth Factor

Abstract We explored the antitumor efficacy of a strategy using recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a xenogeneic protein vaccine, which we have demonstrated to have effective antiangiogenic activities in several tumor models, in combination with low-dose adriamycin in lymphoma model. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomly divided into four groups: combination therapy (xVEGF plus adriamycin), xVEGF treatment alone, adriamycin treatment alone, and normal saline (NS) groups, and received relevant treatments. Tumor growth, survival rate of tumor-bearing mice, and potential toxicity of regimens above were investigated. Anti-VEGF antibodies and anti-VEGF antibody-producing B cells (APBCs) were detected by Western blot analysis and enzyme-linked immunospot (ELISPOT) assay, respectively. In addition, microvessel density (MVD) within tumor tissues and tumor cell apoptosis were determined by immunohistochemistry and TUNEL staining, respectively. Our data showed that combination therapy inhibited tumor growth and improved survival of tumor-bearing mice significantly, and complete regression of tumor was observed in 3 of 10 mice in combination group in EL4 lymphoma model.Survival rate of mice was significantly higher in combination group than that in xVEGF alone group,in adriamycin alone group (P<0.05),or that in NS group (P<0.01). Remarkably, the combination treatment resulted in not only significant antiangiogenic effects but also promotion of tumor cell apoptosis. The calculated indexes of combination therapy showed synergistic relationship in terms of inhibition of tumor growth, antiangiogenesis, induction of tumor cell apoptosis. In addition, anti-VEGF antibodies and APBCs were found in mice treated with either xVEGF vaccine alone or combination treatment. No marked toxicities were found in the treated mice. In summary, these findings may provide an effective combination approach for lymphoma therapy in the future.

scholarly journals Small-Molecule Activation of p53 Blocks Hypoxia-Inducible Factor 1α and Vascular Endothelial Growth Factor Expression In Vivo and Leads to Tumor Cell Apoptosis in Normoxia and Hypoxia

2009 ◽  
Vol 29 (8) ◽  
pp. 2243-2253 ◽  
Author(s):  
Jun Yang ◽  
Afshan Ahmed ◽  
Evon Poon ◽  
Nina Perusinghe ◽  
Alexis de Haven Brandon ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Cell ◽  
Dna Damage Response ◽  
Cell Apoptosis ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Tumor Cell Apoptosis ◽  
Damage Response ◽  
Endothelial Growth Factor

ABSTRACT The p53 tumor suppressor protein negatively regulates hypoxia-inducible factor 1α (HIF-1α). Here, we show that induction of p53 by the small-molecule RITA (reactivation of p53 and induction of tumor cell apoptosis) [2,5-bis(5-hydroxymethyl-2-thienyl) furan] (NSC-652287) inhibits HIF-1α and vascular endothelial growth factor expression in vivo and induces significant tumor cell apoptosis in normoxia and hypoxia in p53-positive cells. RITA has been proposed to stabilize p53 by inhibiting the p53-HDM2 interaction. However, induction of p53 alone was insufficient to block HIF-1α induced in hypoxia and has previously been shown to require additional stimuli, such as DNA damage. Here, we identify a new mechanism of action for RITA: RITA activates a DNA damage response, resulting in phosphorylation of p53 and γH2AX in vivo. Unlike other DNA damage response-inducing agents, RITA treatment of cells induced a p53-dependent increase in phosphorylation of the α subunit of eukaryotic initiation factor 2, requiring PKR-like endoplasmic reticulum kinase activity, and led to the subsequent downregulation of HIF-1α and p53 target proteins, including HDM2 and p21. Through the identification of a new mechanism of action for RITA, our study uncovers a novel link between the DNA damage response-p53 pathway and the protein translational machinery.

scholarly journals Five-year real-world outcomes of anti-vascular endothelial growth factor monotherapy versus combination therapy for polypoidal choroidal vasculopathy in a Chinese population: a retrospective study

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jingyuan Yang ◽  
Mingzhen Yuan ◽  
Erqian Wang ◽  
Song Xia ◽  
Youxin Chen
Keyword(s):  
Combination Therapy ◽  
Real World ◽  
Combination Group ◽  
Vascular Endothelial ◽  
Visual Outcomes ◽  
Anti Vegf ◽  
The Mean ◽  
Endothelial Growth Factor ◽  
Initial Combination

Abstract Background To evaluate 5-year outcomes of anti-vascular endothelial growth factor (VEGF) monotherapy and combination therapy of anti-VEGF agents and photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV) in a real-world Chinese population. Methods Retrospective study. Fifty-three eyes of 46 patients with subtype 1 and 2 PCV followed up for at least 60 months were grouped into three regimens: anti-VEGF monotherapy, PDT combining with anti-VEGF therapy initially, and PDT combining with deferred anti-VEGF therapy. Main outcome measure was best-corrected visual acuity (BCVA) using logarithm of minimal angle of resolution (logMAR). Results The mean BCVA of eyes with subtype 1 PCV (n = 28) deteriorated from 0.69 logMAR at baseline to 1.25 logMAR at months 60 (P = 0.001), while the mean BCVA of eyes with subtype 2 PCV (n = 25) sustained stable from 0.62 logMAR at baseline to 0.57 at months 60 (P = 0.654). No significant differences of visual outcomes were found between the 3 treatment regimens for subtype 1 PCV. Anti-VEGF monotherapy and initial combination treatment had better visual outcomes in eyes with subtype 2 PCV than deferred combination group during part of follow-up significantly. Initial combination group needed a less number of PDT than deferred combination group (P < 0.001). Conclusions Compared with subtype 1 PCV, subtype 2 PCV has a more favorable visual outcome in real world. All the regimens presented unfavorable visual outcomes for subtype 1 PCV. Anti-VEGF monotherapy and initial combination therapy should be superior to deferred combination therapy in the long-term management of subtype 2 PCV. Prospective randomized studies of larger size are needed to determine the long-term efficacy and safety of various treatment for PCV in real world.

scholarly journals Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

2014 ◽  
Vol 204 (2) ◽  
pp. 247-263 ◽  
Author(s):  
Christine Jean ◽  
Xiao Lei Chen ◽  
Ju-Ock Nam ◽  
Isabelle Tancioni ◽  
Sean Uryu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Stromal Cells ◽  
Barrier Function ◽  
Tumor Metastasis ◽  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor

Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.

DC120, a Novel and Potent Inhibitor of AKT Kinase, Induces Tumor Cell Apoptosis and Suppresses Tumor Growth

2012 ◽  
Vol 82 (2) ◽  
pp. 189-198 ◽  
Author(s):  
Rong Deng ◽  
Fen Yang ◽  
Shao-hua Chang ◽  
Jun Tang ◽  
Juan Qin ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Apoptosis ◽  
Potent Inhibitor ◽  
Akt Kinase ◽  
Tumor Cell Apoptosis

scholarly journals Photodynamic therapy combined with anti-vascular endothelial growth factor therapy for pachychoroid neovasculopathy

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248760
Author(s):  
Akiko Miki ◽  
Sentaro Kusuhara ◽  
Tsuyoshi Otsuji ◽  
Yu Kawashima ◽  
Katsuaki Miki ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Photodynamic Therapy ◽  
Growth Factor ◽  
Combination Therapy ◽  
Vascular Endothelial ◽  
Anti Vegf ◽  
Initial Combination Therapy ◽  
Pachychoroid Neovasculopathy ◽  
Endothelial Growth Factor ◽  
Initial Combination

This multicenter retrospective study was conducted to evaluate the 1-year treatment outcome of photodynamic therapy (PDT) combined with anti-vascular endothelial growth factor (VEGF) therapy for pachychoroid neovasculopathy (PNV). A total of 42 eyes of 42 patients with treatment-naïve PNV who were treated with PDT combined with intravitreal injections of an anti-VEGF agent (ranibizumab or aflibercept) for 1 year. All eyes showed exudative and/or hemorrhagic changes that affected the fovea at baseline. After the initial combination therapy, subfoveal choroidal thickness (SCT) and central retinal thickness (CRT) were significantly reduced and were maintained as such for 12 months (P < 0.01 in SCT and CRT). The best-corrected visual acuity (BCVA) (0.19 ± 0.30 at baseline) significantly improved at 3 months (0.15 ± 0.29, P < 0.05) and further improved at 12 months (0.10 ± 0.30, P < 0.01) when compared to that at baseline. After the initial combination therapy, 32 eyes (76.2%) required no additional treatments for 12 months. The mean number of additional PDT and intravitreal injections of anti-VEGF agents was 0.1 ± 0.3 and 0.9 ± 1.9, respectively. Of the 42 eyes included in this study, 22 eyes (52.4%) had polypoidal lesions at baseline. No significant differences in SCT, CRT, or BCVA were observed at any time points between eyes with and without polypoidal lesions. Of 20 eyes without polypoidal lesions, only 1 eye (5.0%) needed additional treatments. PNV, especially without polypoidal lesions, can be treated effectively with PDT combined with anti-VEGF therapy with few sessions.

scholarly journals Antitumor Effect of Periplocin in TRAIL-Resistant Human Hepatocellular Carcinoma Cells through Downregulation of IAPs

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Chieh-Fang Cheng ◽  
I-Huang Lu ◽  
Hsiang-Wen Tseng ◽  
Chung-Yuan Sun ◽  
Li-Tsen Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Apoptosis ◽  
Cardiac Glycosides ◽  
Chinese Herb ◽  
Carcinoma Cells ◽  
Root Bark ◽  
Tumor Cell Apoptosis ◽  
Hepatocellular Carcinoma Cells

Cortex periplocae is the dried root bark ofPeriploca sepiumBge., a traditional Chinese herb medicine. It contains high amounts of cardiac glycosides. Several cardiac glycosides have been reported to inhibit tumor growth or induce tumor cell apoptosis. We extracted and purified cortex periplocae and identified periplocin as the active ingredient that inhibited the growth of TNF-related apoptosis-inducing ligand-(TRAIL-) resistant hepatocellular carcinoma cells. The antitumor activity of periplocin was further increased by TRAIL cotreatment. Periplocin sensitized TRAIL-resistant HCC through the following two mechanisms. First, periplocin induced the expression of DR4 and FADD. Second, the cotreatment of TRAIL and periplocin suppressed several inhibitors of apoptosis (IAPs). Both mechanisms resulted in the activation of caspase 3, 8, and 9 and led to cell apoptosis. In addition, intraperitoneal injection (IP) of periplocin repressed the growth of hepatocellular carcinoma (HCC) in xenograft tumor model in mice. In summary, periplocin sensitized TRAIL-resistant HCC cells to TRAIL treatment and resulted in tumor cell apoptosis and the repression of tumor growthin vivo.

First-in-class cell penetrating proteins targeting Mcl-1 induce tumor cell apoptosis and inhibition of tumor growth in vivo

2016 ◽  
Vol 69 ◽  
pp. S132-S133
Author(s):  
S. Thiolloy ◽  
J. Desmet ◽  
F. Baatz ◽  
S. Loverix ◽  
K. Vandenbroucke ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Cell Apoptosis ◽  
Tumor Cell Apoptosis ◽  
Cell Penetrating ◽  
Inhibition Of Tumor Growth
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