• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10769-10772
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• 2015

Purpose: This analysis was conducted to evaluate cardiovascular toxicity of commonly used anti-VEGF therapeutic agent, bevacizumab, in treating patients with cancer. Methods: Clinical studies evaluating the efficacy and safety of bevacizumab-based regimens on response and safety for patients with cancer were identified using a predefined search strategy, allowing cardiovascular toxicity and other side effects of treatment to be estimated. Results: In bevacizumab based regimens, 4 clinical studies including 282 patients with advanced cancer (including gliomas, cervical, breast and ovarian cancer) were considered eligible for inclusion. These bevacizumab-based regimens included docetaxel, irinitecan and carboplatin. Systematic analysis suggested that, of 282 patients treated by bevacizumab based regimens, hypertension and thrombo-embolism occurred in 2.5% (7/282), while only 3 patients reported cardiovascular events (1.1%). No treatment related death occurred in bevacizumab based treatment. Conclusion: This systemic analysis suggests that bevacizumab based regimens are associated with reasonable and accepted cardiovascular toxicity when treating patients with gliomas, cervical, breast and ovarian cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2453-2459
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• 2013

Bevacizumab has been approved for use in combination with chemotherapy to treat many types of cancer but associated neutropenic events, including febrile neutropenia, have been reported. To estimate the incidence and relative risk of neutropenic events in cancer patients treated with bevacizumab combination therapy, we searched PubMed, EMBASE, and Web of Science literature databases, as well as abstracts presented at the American Society of Clinical Oncology conferences, to identify relevant studies published from January 1966 to December 2011. Studies that compared bevacizumab plus chemotherapy or biological therapy with chemotherapy or biological therapy alone, and that had adequate safety data profiles, were selected for analysis. Statistical analyses were conducted to calculate the summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effects models. A total of 22 clinical trials involving 15,056 patients were included in the analysis. The summary incidences of high-grade neutropenia (HGN) and high-grade febrile neutropenia (HGFN) in patients receiving bevacizumab was 27.3% (95% CI: 26.4%-28.3%) and 3.91% (95% CI: 3.51%-4.37%), respectively. The risks of HGN (RR=1.10; 95% CI: 1.02-1.19; P=0.02) and HGFN (RR=1.31; 95% CI: 1.08-1.59; P=0.005) were significantly increased in bevacizumab-treated patients, compared to those who did not receive bevacizumab. The RR of bevacizumab-associated HGN, but not HGFN, varied significantly with tumor types (P=0.005). The increased risk of bevacizumab-associated neutropenic events was dose-dependent, as the RR was greater at a dose of 5 mg/kg/week than at 2.5 mg/kg/week. Our findings suggest that bevacizumab addition to cancer therapy significantly increases the risk of serious neutropenic events, and this risk may be dose-dependent.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6559-6564
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• 2014

Objective: To evaluate the efficacy and safety of bevacizumab in the treatment of patients with metastatic colorectal cancer (mCRC). Methods: In a single-center, observational study of 91 Chinese patients with mCRC who received bevacizumab in combination with chemotherapy was conducted. Objective response rates (ORRs), progression-free survival (PFS), overall survival (OS) and adverse events were recorded, and the relationships between various clinical factors and PFS or OS were evaluated by Cox proportional hazards models. Results: Treatment with bevacizumab and chemotherapy was effective and tolerable. Univariate analysis showed that PFS and OS were significantly associated with the Eastern Cooperative Oncology Group performance status (ECOG-PS) score, duration of bevacizumab exposure, and whether chemotherapy was continued after discontinuation of bevacizumab treatment. A multivariate analysis showed that the duration of bevacizumab exposure and whether chemotherapy was continued after discontinuation of bevacizumab were independent prognostic factors for PFS and OS. Conclusion: In Chinese mCRC population, the shorter the duration of exposure to bevacizumab and chemotherapy, the worse the prognosis is.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.35 no.2
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• pp.66-73
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• 2009

Tumor angiogenesis is a process leading to formation of blood vessels within tumors and is crucial for maintaining a supply of oxygen and nutrients to support tumor growth and metastasis. Vascular endothelial growth factor(VEGF) plays a key role in tumor angiogenesis including induction of endothelial cell proliferation, migration, survival and capillary tube formation. VEGF binds to two distinct receptors on endothelial cells. VEGFR-2 is considered to be the dominant signaling receptor for endothelial cell permeability, proliferation, and differentiation. Bevacizumab(Avastin, Genetech, USA) is a monoclonal antibody against vascular endothelial growth factor. It is used in the treatment of cancer, where it inhibits tumor growth by blocking the formation of new blood vessels. The goal of this study is to identify the anti-tumor effect of Bevacizumab(Avastin) for oral squamous cell carcinoma cell lines. Human squamous cell carcinoma cell line(HN4) was used in this study. We examined the sensitivity of HN4 cell line to Bevacizumab(Avastin) by using in vitro proliferation assays. The results were as follows. 1. In the result of MTT assay according to concentration of Bevacizumab(Avastin), antiproliferative effect for oral squamous cell carcinoma cell lines was observed. 2. The growth curve of cell line showed the gradual growth inhibition of oral squamous cell carcinoma cell lines after exposure of Bevacizumab(Avastin). 3. In the apoptotic index, groups inoculated Bevacizumab(Avastin) were higher than control groups. 4. In condition of serum starvation, VEGFR-2 did not show any detectable autophosphorylation, whereas the addition of VEGF activated the receptor. Suppression of phosphorylated VEGFR-2 and phosphorylated MAPK was observed following treatment with Bevacizumab(Avastin) in a dose-dependent manner. 5. In TEM view, dispersed nuclear membrane, scattered many cytoplasmic vacuoles and localized chromosomal margination after Bevacizumab(Avastin) treatment were observed. These findings suggest that Bevacizumab(Avastin) has the potential to inhibit MAPK pathway in proliferation of oral squamous cell carcinoma cell lines via inhibition of VEGF-dependent tumor growth.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.4
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• pp.357-363
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• 2015

The purpose of this study was to compare the inhibitory effect of bevacizumab on human Tenon's fibroblasts (HTFs) cultured from primary and recurrent pterygium. Cultured HTFs were exposed to 2.0, 5.0, 7.5, and 15.0 mg/mL concentration of bevacizumab for 24 hours. The 3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase leakage assays were then performed to assess fibroblast metabolism and viability. The matrix metalloproteinase (MMP), procollagen type I C terminal propeptide (PIP), and laminin immunoassays were performed to examine extracellular matrix production. Changes in cellular morphology were examined by phase-contrast and transmission electron microscopy. Both metabolic activity and viability of primary and recurrent pterygium HTFs were inhibited by bevacizumab in a dose-dependent manner, especially at concentrations greater than 7.5 mg/mL. Both types of HTFs had significant decreases in MMP-1, PIP, and laminin levels. Distinctly, the inhibitory effect of bevacizumab on MMP-1 level related with collagenase in primary pterygium HTFs was significantly higher than that of recurrent pterygium. Significant changes in cellular density and morphology both occurred at bevacizumab concentrations greater than 7.5 mg/mL. Only primary pterygium HTFs had a reduction in cellular density at a bevacizumab concentration of 5.0 mg/mL. Bevacizumab inhibits primary and recurrent pterygium HTFs in a dose-dependent manner, especially at concentrations greater than 7.5 mg/mL. As the primary HTFs produces larger amounts of MMP-1 compared to recurrent HTFs, significant reduction in MMP-1 level in primary pterygium HTFs after exposure to bevacizumab is likely to be related to the faster cellular density changes in primary pterygium HTFs.

• BMB Reports
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• v.42 no.12
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• pp.800-805
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• 2009

This study investigated the effect of subconjunctival injections of bevacizumab, an anti-VEGF antibody, on processes involved in corneal wound healing after alkali burn injury. Mice were divided into three groups: Group 1 was the saline-treated control, group 2 received subconjunctival injection of bevacizumab 1hr after injury and group 3 received bevacizumab 1 hr and 4 days after injury. Cornea neovascularization and opacity were observed using a slit lamp microscope. Corneal repair was assessed through histological analysis and immunostaining for CD31, $\alpha$-SMA, collagen I, and TGF-$\beta$2 7 days post-injury. In group 3, injection of bevacizumab significantly lowered neovascularization and improved corneal transparency. Immunostaining analysis demonstrated a reduction in CD31, $\alpha$-SMA and TGF-$\beta$2 levels in stroma compared to group 1. These results indicate that bevacizumab may be useful in reducing neovascularization and improving corneal transparency following corneal alkali burn injury by accelerating regeneration of the basement membrane.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6501-6506
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• 2015

There are numerous clinical cases indicating that long-term use of bevacizumab may increase the invasiveness of tumors. However, to date, little is known about underlying molecular mechanisms. Therefore, the purpose of our study was to investigate effects of bevacizumab in four cancer cells lines (WSU-HN6, CAL27, Tca83, and HeLa). It was found to promote migration and invasion in the WSU-HN6 and Tca83 cases, while exerting inhibitory effects in CAL27 and HeLa cells. The signal transducer and activator of transcription (STAT) 3 inhibitors niclosamide and S3I-201 inhibited the STAT3 signal pathway, which is activated by bevacizumab. These inhibitors also substantially blocked bevacizumab-induced migration of WSU-HN6 and Tca83 cells. Bevacizumab upregulated interleukin (IL)-6 and phosphorylated (p)-STAT3 expression time-dependently. Therefore, we propose that bevacizumab has differential effects on the migration of different cancer cell lines and promotes migration via the IL-6/STAT3 signaling pathway.

• Korean Journal of Clinical Pharmacy
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• v.30 no.4
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• pp.234-242
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• 2020

Background: Bevacizumab-induced proteinuria is known to occur when vascular endothelial cell receptors are blocked, which leads to decreased protein filtration. Although several studies have analyzed the correlation between therapeutic effect of bevacizumab and proteinuria, no conclusion has been established. Methods: In this retrospective study, colorectal cancer patients who received bevacizumab and urinary protein check from January 2015 to December 2016, were included. The incidence of proteinuria and the grade according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0 were evaluated after bevacizumab administration. The primary objective was to correlate proteinuria with overall response rate (ORR) and time to progression (TTP). Primary lesion, metastasized organs, surgery or radiation therapy, chemotherapy were investigated for analysis of risk factors for proteinuria development. Results: A total of 149 patients included in the analysis. Proteinuria occurred 19.5% (n=29) in the study patients; 20 in grade 1, 7 in grade 2, and 2 in grade 3. ORR was 55.2% in the proteinuria group and 51.7% in the non-proteinuria group. There was no difference between two groups (p=0.89). The TTP through the survival curve was similar in both groups (10 months, p=0.97). The risk of proteinuria was high in patients who had liver metastasis (p=0.02) and no surgery (p=0.01). Conclusions: These result indicates that bevacizumab-induced proteinuria expression was not correlated with the therapeutic effect on patients with colorectal cancer. Further analysis is required to find out the correlation between proteinuria and therapeutic effects. The risk of proteinuria was increased from patients who had liver metastasis, and no surgery.

• BMB Reports
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• v.46 no.4
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• pp.195-200
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• 2013

To understand the corneal regeneration induced by bevacizumab, we investigated the structure changes of stroma and basement membrane regeneration. A Stick soaked in 0.5 N NaOH onto the mouse cornea and 2.5 mg/ml of bevacizumab was delivered into an alkali-burned cornea (2 ${\mu}l$) by subconjunctival injections at 1 hour and 4 days after injury. At 7 days after injury, basement membrane regeneration was observed by transmission electron microscope. Uneven and thin epithelial basement membrane, light density of hemidesmosomes, and edematous collagen fibril bundles are shown in the alkali-burned cornea. Injured epithelial basement membrane and hemidesmosomes and edematous collagen fibril bundles resulting from alkali-burned mouse cornea was repaired by bevacizumab treatment. This study demonstrates that bevacizumab can play an important role in wound healing in the cornea by accelerating the reestablishment of basement membrane integrity that leads to barriers for scar formation.

• Korean Journal of Ophthalmology
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• v.32 no.6
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• pp.451-458
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• 2018

Purpose: To investigate the efficacy, safety, and anatomical outcomes associated with intravitreal anti-vascular endothelial growth factor (VEGF) treatment of retinopathy of prematurity (ROP). Methods: We performed a retrospective review of intravitreal anti-VEGF (bevacizumab or ranibizumab) treatment of 153 eyes (83 infants) diagnosed with ROP at two tertiary hospitals from June 2011 to January 2017. The primary outcome was the rate of recurrence requiring additional treatment; secondary outcomes included incidence of major complications and final refractive error. Results: A total of 101 eyes were treated with bevacizumab, and 52 with ranibizumab. The bevacizumab and ranibizumab groups were characterized by mean birthweights of $941.8{\pm}296.1$ and $1,257.7{\pm}514.5g$, gestational ages at birth of $26.9{\pm}1.9$ and $28.1{\pm}3.2$ weeks, and postmenstrual ages at treatment of $40.4{\pm}2.4$ and $39.2{\pm}2.3$ weeks, respectively. The two groups differed significantly in birthweights and gestational ages at birth, but not in postmenstrual ages at treatment. The mean follow-up duration was $30.9{\pm}18.4$ months for the bevacizumab group, and $13.9{\pm}12.5$ months for ranibizumab. More cases were classified as zone 1 ROP in the ranibizumab group (44.2% vs. 11.9%, p < 0.001). Major surgical interventions included scleral encircling and vitrectomy (one and two eyes, respectively, both in the bevacizumab group). Retinal detachment was noted in one eye treated with bevacizumab. There was no significant difference in the most recent spherical equivalence for the two groups ($+0.10{\pm}3.66$ and $+0.22{\pm}3.00$ diopters for bevacizumab and ranibizumab, respectively). Univariable analysis revealed that only ROP stage influenced the occurrence of major complications (odds ratio, 9.046; p = 0.012). Conclusions: Intravitreal anti-VEGF treatment of ROP with both bevacizumab and ranibizumab achieved stable retinal vascularization with a low rate of complications and recurrence. Ranibizumab achieved similar anatomical outcomes as bevacizumab, without additional risk for major complications.