Endothelial Growth Factor Therapy Research Articles

Safety and Efficacy of Ranibizumab and Bevacizumab for the Treatment of Neovascular Age-related Macular Degeneration

Ocular anti-vascular endothelial growth factor (VEGF) therapy represents a major breakthrough in the treatment of patients with neovascular age-related macular degeneration (nvAMD). The anti-VEGF agents, ranibizumab and bevacizumab, are both widely used in the treatment of nvAMD although bevacizumab has not yet received regulatory approval for intraocular use. Bevacizumab costs considerably less than ranibizumab when administered as an intraocular injection, which has led to widespread use and studies comparing the efficacy and safety of the two drugs. Bevacizumab shares identical pharmacology with ranibizumab although structural differences result in differences in receptor affinity and rates of drug clearance. While estimates of the vitreous half-life of ranibizumab vary, it is shorter than that of bevacizumab. Furthermore, the serum half-life of bevacizumab is about 20 days, more than twice that of ranibizumab and this has led to speculation that it may present a greater risk of systemic adverse effects. Considerable clinical trial evidence exists relating to the efficacy and safety of ranibizumab. The Comparison of age-related macular degeneration treatments trials (CATT) study of the two drugs found efficacy to be equivalent for the as needed versus as needed and monthly versus monthly comparisons. Ranibizumab as needed was equivalent to monthly ranibizumab, though the bevacizumab as needed was not equivalent to monthly bevacizumab. A greater number of serious adverse events (SAEs) occurred with bevacizumab. However, the study was insufficiently powered to identify differences in drug-related adverse events. Intravitreal injection of bevacizumab is associated with a low but significant risk of acute intraocular inflammation, shown to result in significant visual loss in some patients. Finally, there are issues related to fractionating of bevacizumab that has lead to sporadic cases of blindness worldwide. The increased risk for both systemic and ocular adverse events may influence the cost-effectiveness ratio of the two drugs based on health economic models. Further comparative studies and continuous monitoring of safety data are required to examine the incidence of adverse events.

P3-04-02: Bevacizumab Treatment Alters Intrinsic Subtypes in a VEGF-Reinforced Xenograft Model of ER-Positive Breast Cancer.

Abstract Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy improves disease-free but not overall survival in metastatic breast cancer. To seek further insight on resistance to anti-VEGF antibody bevacizumab (BEV) at the molecular level, we developed breast cancer xenograft models allowing comparison of tumor response at different time-points. Here we report the gene expression and miRNA analyses of response and non-response to BEV in these models. Methods: MCF-7 cells transfected with control vector (ML20) or VEGF (MV165) were implanted into the mammary fat pads of athymic mice. Tumors from short-term treatment with BEV (3 weeks; Responders to BEV, R) or long-term treatment (8 weeks; Non-Responders, NR) or with vehicle control group (V) were subjected to whole-genome gene expression analysis (Human WG-6v2 Expression Beadchips, Illumina) and miRNA profiling (TaqMan ArrayHuman MicroRNA A+B Cards Set v3.0, Applied Biosystems).Validation of the chosen genes was performed using quantitative real-time RT-PCR (qRT-PCR) and Immunohistochemistry (IHC). Results: Short-term treatment to BEV (3 weeks; 5 mg/kg, i.p./twice weekly) inhibited primary tumor growth significantly in MV165 xenografts compared with vehicle control, whereas BEV treatment did not affect the tumor growth in the ML20 model. MV165 xenografts progressed after 8 weeks of BEV treatment. Gene set enrichment analysis (GSEA) revealed that luminal A-related gene sets were enriched in MV165-R compared to MV165-NR group including DESMEDT (ESR1), SMID_Breast_Cancer_Luminal_A_up, and MASSARWEH_ Tamoxifen_Resistance_ Down. Myoepithelial-specific gene sets were upregulated in both the R and NR groups compared with the vehicle group. qRT-PCR analysis showed that estrogen receptor alpha (ESR1) representative for luminal A decreased significantly in the MV-165-NR group (P=0.001) compared to vehicle. In contrast, Cytokeratin 5 (KRT5) levels increased significantly in both R (P=0.02) and NR (P=0.03) groups. In addition, KRT14 was upregulated in R (P= 0.04) and in NR (P=0.14) group in comparison with the vehicle group, suggesting the upregulation of myoepithelial phenotype specific to BEV treated MV165 model, but not ML20 model. Similar results were obtained by IHC. Consistent with mRNA changes, ESR1 regulated miRNA such as miR-107 (P=0.007) and miRNA important in tamoxifen resistance such as mir-451 (P= 0.0003) were also altered in MV165-NR group compared to vehicle. Conclusion: These results suggest that treatment with BEV may alter the intrinsic subtypes in the presence of VEGF expression. These data may help to explain the variable results to anti-VEGF therapy based on the duration of BEV treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-04-02.

Color vision in an elderly patient with protanopic genotype and successfully treated unilateral age-related macular degeneration

We investigated differences in color discrimination between the fellow eye and the affected eye successfully treated for unilateral age-related macular degeneration (AMD) in a 69-year-old male patient with protanopia. His best-corrected visual acuity (BCVA) was 1.2 in the right eye (RE) and 0.2 in the left eye (LE). Fundus and angiographic findings showed classic choroidal neovascularization (CNV) secondary to AMD in the LE. BCVA of the LE improved to 0.4, and CNV resolved by 15months after initiating combined anti-vascular endothelial growth factor and photodynamic therapies. After CNV closure, the Farnsworth dichotomous was performed, showing confusion patterns of the protan axis in either eye. The Farnsworth-Munsell 100-hue test showed a total error score of 520 in the LE, much higher than the score of 348 in the RE. Complete genotypes of the long-wavelength-sensitive (L-) cone and middle-wavelength-sensitive (M-) cone opsin genes were determined by polymerase chain reaction, revealing that the patient had a single 5' L-M 3' hybrid gene (encoding an M-cone opsin), with this genotype responsible for protanopia (the L-cone opsin gene was non-functional), instead of the L-cone and M-cone opsin gene arrays. Poorer color vision discrimination in the LE than the RE remained present despite closure of CNV. The presence and type of congenital color vision defect can be confirmed using molecular genetic testing even if complications of acquired retinal diseases such as AMD are identified.

An Evidence-Based Approach to the Use of Predictive Biomarkers in the Treatment of Non- Small Cell Lung Cancer (NSCLC)

Recent advances in the treatment of non-small cell lung cancer (NSCLC) have led to improvements in patient survival and quality of life. It is unclear whether molecular abnormalities associated with NSCLC cell survival, growth and proliferation are useful in predicting treatment benefit. We conducted a systematic review to establish which biomarkers contribute meaningfully to the management of NSCLC. A team of researchers searched PubMed and conference proceedings (ASCO, ESMO, IASLC, USCAP) using MESH terms for NSCLC and randomized trials (RCT), plus keywords for variables of interest. Evidence from multiple RCTs confirmed that histologic subtype is prognostic for survival and predictive of treatment efficacy and/or toxicity in NSCLC. Likewise, activating mutations of the epidermal growth factor receptor (EGFR) are associated with benefit from EGFR tyrosine kinase inhibitors in patients with advanced non-squamous NSCLC and should be assessed routinely. No biomarkers to date reliably predict response to anti-Vascular Endothelial Growth Factor (VEGF) therapies. There are inconsistent data on the role of ERCC1, BRCA, Beta tubulin III, RRM1, K-RAS, or TP-53 in treatment decisions. These tests should not be routinely used in selecting treatment at this time, whereas EML4/ALK translocations predict responses to specific targeted agents, the optimal assessment of this molecular abnormality has yet to be established. Personalized care of patients with NSCLC based on biomarkers is increasingly important to both clinical practice and research.

Surgical Treatment of Age-Related Macular Degeneration

Choroidal neovascularization (CNV) and geographic atrophy (GA) are serious and potentially devastating complications of age-related macular degeneration (AMD), a leading cause of blindness in the developed world. While anti-vascular endothelial growth factor (VEGF) therapies have emerged as the current standard treatment of choice for choroidal neovascularization, the requirement for indefinite injections places a tremendous burden on physicians and patients, and may have disappointing outcomes in hemorrhagic neovascular AMD. No superior agents exist to treat large subretinal hemorrhage and geographic atrophy. Over the years, several vitreoretinal surgical approaches have been developed to treat macular degeneration, and these surgical options may still play a role in the management of specific complications of AMD. This review summarizes the principles, techniques, and results of surgical treatments for neovascular and non-neovascular age-related macular degeneration, with emphasis on submacular surgery for removal of CNV, full and limited macular translocation, retinal pigment epithelium, and choroid transplants as well as treatment of thick subretinal hemorrhage.

Abstract P6-12-01: A Meta Analysis of Risk of Cardiovascular Events in Patients with Metastatic Breast Cancer (MBC) Treated with Anti Vascular Endothelial Growth Factor (VEGF) Therapy — Bevacizumab

Abstract Background and objectives: Bevacizumab, used in combination with chemotherapy has demonstrated efficacy in randomized trials in MBC. Hypertension, congestive heart failure and cardiomyopathy have been reported in trials of bevacizumab in breast cancer. The aim of this systematic review and meta analysis is to determine the overall risk of grade 3-4 hypertension (HTN), left ventricular dysfunction (LVD) and venous (VT) and arterial thromboembolic events (ATE) related to Bevacizumab in patients with MBC. Methods: We selected randomized phase III trials which compared chemotherapy with or without bevacizumab in MBC as first or second line therapy. Data extraction was carried out from results published in the literature or from conference proceedings of the selected studies. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. We collected all grade 3-4 events reported in these trials in relation to cardiovascular events: HTN, LVD, congestive heart failure, cardiomyopathy, VT and ATE. Results: Five trials were included in the meta-analysis: E2100, AVADO, RIBBON-1, RIBBON-2 and Miller et al study (capecitabine alone or plus bevacizumab in previously treated MBC). In total 2126 patients received chemotherapy in combination with bevacizumab and 1444 chemotherapy alone. When there was tendency for heterogeneity, random-effects models were used. Thromboembolic events were pooled together as VT and ATE as information was not clear in some of the reported studies. CHF and cardiomyopathy were considered for LVD events in the Miller study as LVD was not reported. Patients treated with bevacizumab-containing regimens had a RR for HTN of 10.32 (95% CI, 4.23- 24.79; p<.0001), RR for LVD 2.58 (95% CI, 1.06 - 6.32; p=0.04) and RR for VT and ATE of 1.71 (95% CI, 0.81- 3.60; p=0.16) as shown in figure 1. Conclusion: HTN is a recognized side effect of bevacizumab therapy. The risk of LVD is also significantly higher with bevacizumab therapy (RR 2.58) as shown in this pooled analysis, but the risk of thrombotic events is not increased. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-12-01.

Session 6 introduction

Session 6 introduction

Investigation of pathways regulating early antiangiogenic response to bevacizumab given prior to neoadjuvant breast cancer chemotherapy.

TPS176 Background: There are no proven biomarkers of efficacy of anti-vascular endothelial growth factor (VEGF) therapies. The vast majority of these drugs are investigated in patients with advance...

Intravitreal anti‐vascular endothelial growth factor therapy with bevacizumab for tuberous sclerosis with macular oedema

To describe two patients with macular oedema secondary to tuberous sclerosis complex (TSC) who were treated with intravitreal bevacizumab injection. Interventional case reports. Bevacizumab 1.25 mg was injected into the vitreous of two patients with TSC-associated macular oedema / exudative retinal detachment. Vascular endothelial growth factor (VEGF) concentration in the vitreous fluid was measured by enzyme-linked immunosorbent assay (ELISA) in one of these patients. Patient 1: a 22-year-old woman with TSC was diagnosed as having multiple retinal hamartomas in both eyes. Eleven years later, the patient developed macular oedema with epiretinal membrane formation in the right eye. The patient underwent pars-plana vitrectomy with retinal photocoagulation for retinal tumours. VEGF concentration in the vitreous fluid was high compared to that in patients without retinal vascular diseases. Recurrent macular oedema disappeared by intravitreal injection of bevacizumab. Patient 2: a 32-year-old woman with TSC-associated retinal hamartoma, temporally showing macular exudative retinal detachment, developed neovascularization originated from the tumour. By intravitreal bevacizumab injection, the tumour size reduced markedly with regression of neovascularization. These results suggest that VEGF derived from retinal hamartomas causes macular oedema associated with TSC. Intravitreal injections of bevacizumab may be a useful therapeutic option for macular oedema secondary to TSC.

Abstract 368: In vivo vessel co-option by glioma cells following chronic anti-angiogenic treatment

Abstract Introduction: Anti-vascular endothelial growth factor (VEGF) therapy using monoclonal antibodies or multitargeted tyrosine kinase inhibitors (TKIs) has shown modest efficacy in recurrent Glioblastoma Multiforme (rGBM). In some orthotopic murine models, increased survival with these agents can primarily be attributed to a reduction in edema rather any direct anti-tumor effect (W. Kamoun et al, JCO 2009). Furthermore, reports have suggested gliomas may respond to anti-angiogenic therapy with an increased invasive phenotype although direct evidence has not yet been established. Here, we used intravital multiphoton laser scanning microscopy (MPLSM) and several orthotopic invasive tumor models to test the invasive tumor response of glioblastoma cells to two anti-angiogenic agents: cediranib and sunitinib. Materials and Methods: We transfected CNS1 (rat glioma) and GL261 (mouse glioma) with DsRed fluorescent protein and maintained the cells in culture as neurospheres. Using mice with surgically implanted cranial windows, we injected 10,000 tumor cells into the cerebrum of SCID (CNS1 cells/xenograft) or C57/b6 (GL261/syngeneic) mice. When tumors had established a primary lesion as determined by intravital microscopy, we treated animals with 6 mg/kg cediranib or 40 mg/kg sunitinib (daily oral gavage) with control groups treated with the corresponding drug vehicle. Tumor cell dynamics relative to brain microvessels were measured with MPLSM using a fluorescence angiography. Following treatment and imaging, we assessed brain sections with immunohistochemistry (IHC). Results: We found that chronic treatment (2 week) of CNS1 tumors with cediranib led to a marked increase of vessel co-option (direct migration of tumor cells along microvessels) compared to control determined both in vivo (+67%) and with IHC (+80%). In vivo imaging revealed perivascular tumor invasion deep into the cortex allowing for time-lapse imaging of tumor cell motility. Using IHC, we measured co-opted regions extended over 1 mm from the primary lesion. Co-opted vessels appeared relatively normal although astrocyte/endothelial cell contact seemed to be disrupted. We confirmed this increase in vessel co-option during anti-angiogenic therapy using sunitinib treatment in CNS1 tumors (5/5 treated) and using cediranib in GL261 tumors (6/8 treated, 2/8 controls). Discussion: With the recent US approval of bevacizumab for treatment of rGBM, anti-VEGF therapy in these tumors may become the standard of care. It is therefore critical to understand the tumor response to this therapy. Here, we find that long-term treatment of established GBMs with anti-angiogenic TKIs leads to an increase in tumor invasion along existing brain vessels. This model provides a foundation for dynamic imaging of this process and for further investigation of the mechanisms governing tumor co-option in the brain. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 368.

Effects of Pegaptanib Sodium on Retinal Function in Isolated Perfused Vertebrate Retina

Purpose: To evaluate the short-term toxic effects of pegaptanib sodium on retinal function. At present, intraocular anti-vascular endothelial growth factor (VEGF) therapy is the primary choice of treatment for neovascular maculopathy. The isoform VEGF165 is specifically inhibited by pegaptanib sodium. Therefore, since VEGF165 has neuroprotective effects against apoptosis of neuronal cells, blockage of VEGF165 by pegaptanib could induce retinal dysfunction. In the present study, we used an electrophysiological technique for testing retinal toxicity in order to evaluate the short-term toxic effects of pegaptanib sodium on retinal function in a model of isolated perfused vertebrate retina.Methods: Isolated bovine retinas were perfused with an oxygenated, pre-incubated nutrient solution. Electroretinograms (ERGs) were recorded as trans-retinal potentials using Ag/AgCl electrodes. Pegaptanib sodium (0.006, 0.06, or 0.2 mg/ml) and solvent carrier were added to the nutrient solution for 45 min. ERGs were monitored before, during, and after exposure.Results: No significant reductions of b-wave (p = 0.357, p = 0.31, and p = 0.11, respectively) or a-wave (p = 0.189, p = 0.46, and p = 0.23, respectively) amplitudes were detected during application of pegaptanib (0.006, 0.06, or 0.2 mg/ml). The solvent carrier alone had no effect on ERG b- or a-waves (p = 0.98 and p = 0.42, respectively). During washout, ERG amplitudes of all test series remained unchanged.Conclusion: Results suggest that both pegaptanib sodium and its solvent carrier have good safety profiles. Intraocular application of 0.3 mg pegaptanib sodium induced no significant changes in ERGs in our ex vivo model and, thus, appears to be safe.

Surgery for peripapillar choroidal neovascularization

The therapy of choroidal neovascularizations (CNVs) in wet age-related macular degeneration (AMD) developed to an anti-vascular endothelial growth factor (VEGF) therapy. Peripapilar CNV (PPCNV) represents another manifestation of CNV which may treated additionally by surgical extraction of the membranes. METHODS: In this retrospective study, the morphological and visual outcome after surgery of 9 eyes of 9 patients with PPCNV was evaluated. RESULTS: Surgery was successful in each patient and visual acuity remaind stable or improved in each patient by two or more lines. Recurrence was observed in 6 eyes within three years. DISCUSSION: Hence, surgery may represent an alternative approach in the therapy of PPCNV although only a small number of cases were included. Randomized prospective trials comparing surgical excision of PPCNV with anti-VEGF therapy alone or in combination are needed.

Circulating biomarkers of bevacizumab activity in patients with breast cancer

Purpose: Noninvasive markers of anti-vascular endothelial growth factor (VEGF) therapy are needed. Soluble vascular cell adhesion molecule (sVCAM-1), soluble VEGF receptor-2 (sVEGFR-2), and plasma VEGF levels were assessed as potential biomarkers of therapy with bevacizumab. Tumor samples were evaluated for VEGFR-2 mutations before and after bevacizumab.Experimental Design: Twenty-one patients with breast cancer underwent neoadjuvant treatment with bevacizumab for 1 cycle followed by 6 cycles of bevacizumab, chemotherapy, and filgrastim. Peripheral blood samples were collected at baseline, post cycles 1, 4 and 7. sVCAM-1, VEGF and sVEGFR-2 levels were measured by enzyme-linked immunosorbent assay (ELISA). Exons 17-26 of VEGFR-2 were sequenced on tissue samples from 20 patients at baseline and post cycle 1 to evaluate for tumor mutations.Results: From baseline to post cycle 1, sVCAM-1 and sVEGFR-2 values increased by a median of 180.5 ng/ml (p

Clinical evaluation of nitric oxide responses to anti-VEGF therapy with bevacizumab

14039 Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has been linked to hypertension (HTN) and arterial thrombo-embolic events that may involve changes in nitric oxide (NO) bioavailability. Methods: 25 patients (pts) with advanced cancer, normal renal function and blood pressure (BP), no increased risks for anti-VEGF toxicities, and not on medications known to confound biomarker studies (including anti-hypertensives) were treated with bevacizumab (BV) 15mg/kg d1, then 10mg/kg q2 week. Prior to biomarker assessment, all patients were placed on a calorie-, nitrate-, and salt-restricted diet for 72 hr. All measures were taken pre-treatment (preRx) and on day 28 of treatment (onRx). Dependant variables included; a) Brachial artery reactivity (BAR) following hyperemic flow stimulus (endothelium-dependent) and sub-lingual nitroglycerine (NTG; endothelium-independent); b) exhaled and plasma/urine total NO2/NO3 using chemiluminescence (Sievers 280NOA) with either KI or VCl3 in HCl as the reductants; c) blood pressure. Additionally, we measured multiple regulators of vascular tone and injury. Comparisons were analyzed using Spearman signed rank tests. Results: Of 25 pts (16 F, 9 M) treated, 21 patients were fully evaluable. Significant changes or strong trends were observed upon comparing preRx vs. onRx for BP (SBP +12.4, DBP +5.6, MAP +7.9 mm Hg), and flow-mediated BAR (-2.0%) with no changes in hyperemic flow/shear stimulus or smooth muscle function (BAR NTG), indicating a decrease in brachial artery endothelial responsiveness. Exhaled NO decreased (-0.8% d1vs d28 and -0.6% pre/post infusion day1). Measurement and data analysis of urinary/plasma NO2/NO3, as well as angiogenic markers, are almost complete and will be reported. Conclusions: After one month of treatment, BV increased BP and decreased endothelium- dependent BAR and exhaled NO, suggesting potentially broad, mechanism-based effects on NO bioavailability in patients. [Table: see text]

Novel Drug Delivery System for Age-related Macular Degeneration Using Nanotechnology

Age-related macular degeneration (AMD) is a leading cause of legal blindness in developed countries. Even with the recent advent of several treatment options such as photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) therapy for the treatment of exudative AMD, characterized by choroidal neovascularization (CNV), their efficacy is still limited. Thus, in this review article, we investigated novel drug delivery system for AMD using nanotechnology. Polyion complex (PIC) micelle has a size range of several tens of nanometers formed through electrostatic interaction, and accumulates in solid tumors through enhanced permeability and retention (EPR) effect. The distribution of the PIC micelle encapsulating fluorescein isothiocyanate-labeled poly-l-lysine (FITC-P(Lys)) in experimental CNV in rats was investigated. PIC micelle accumulates in the CNV lesions and is retained in the lesion for as long as 168 h after intravenous administration. PIC micelles can be used for achieving effective drug delivery system to CNV. Although PDT is a main treatment option for CNV, most patients require repeated treatments. For effective PDT against AMD, the selective delivery of photosensitizer to the CNV lesions and an effective photochemical reaction at the CNV site are necessary. The characteristic dendritic structure of the photosensitizer prevents aggregation of its core sensitizer, thereby inducing a highly effective photochemical reaction. A supramolecular nanomedical device, i.e., a novel dendritic photosensitizer encapsulated by a polymeric micelle formulation was employed for an effective PDT for AMD. With its highly selective accumulation on CNV lesions, this treatment resulted in a remarkably efficacious CNV occlusion with minimal unfavorable phototoxicity. Our results will provide a basis for an effective approach to PDT for AMD.

Single-Chain Bifunctional Vascular Endothelial Growth Factor (VEGF)-Follicle-Stimulating Hormone (FSH)-C-Terminal Peptide (CTP) Is Superior to the Combination Therapy of Recombinant VEGF plus FSH-CTP in Stimulating Angiogenesis during Ovarian Folliculogenesis

Infertility technologies often employ exogenous gonadotropin therapy to increase antral follicle production. In an effort to enhance ovarian response, several long-acting FSH therapies have been developed including an FSH-C-terminal peptide (CTP), where the FSH subunits are linked by the CTP moiety from human chorionic gonadotropin, which is responsible for the increased half-life of human chorionic gonadotropin. We found that administration of FSH-CTP for ovarian hyperstimulation in rats blunted ovarian follicle vascular development. In women, reduced ovarian vasculature has been associated with lower pregnancy rates. We were interested in determining whether vascular endothelial growth factor (VEGF) therapy could enhance ovarian angiogenesis in FSH-CTP-treated rats. Coadministration of systemic FSH-CTP plus recombinant VEGF was compared with treatment with a novel, single-chain bifunctional VEGF-FSH-CTP (VFC) analog. For VFC, the FSH portion targets the protein to the ovary and stimulates follicle growth, whereas VEGF enhances local vascular development. Both in vitro and in vivo studies confirm the dual FSH and VEGF action of the VFC protein. Evaluation of ovarian follicle development demonstrates that administration of combination therapy using VEGF and FSH-CTP failed to increase follicle vasculature above levels seen with FSH-CTP monotherapy. However, treatment with VFC significantly increased follicle vascular development while concurrently increasing the number of large antral follicles produced. In conclusion, we report the production and characterization of a long-acting, bifunctional VEGF-FSH-CTP protein that is superior to combination therapy for enhancing VEGF activity in the ovary and stimulating follicular angiogenesis in rats.

Improving delivery of antineoplastic agents with anti‐vascular endothelial growth factor therapy

It is believed that impairments in delivery of antineoplastic agents to solid tumors result from abnormalities of the tumor microenvironment. Vascular endothelial growth factor (VEGF), the prototypical angiogenic molecule, is one of the main factors responsible for the development and maintenance of the aberrant tumor vascular network, which is characterized by chaotic, leaky blood vessels with high interstitial fluid pressure and inefficient blood flow. The authors proposed that anti-VEGF therapy would reduce the elevated interstitial fluid pressure in tumors, thereby improving blood flow and potentially improving delivery of cytotoxic agents to tumor cells. For the current report, the authors reviewed characteristics of the abnormal tumor vasculature created under the influence of VEGF, the resulting tumor microenvironment, how the tumor microenvironment may impede delivery of antineoplastic agents, and how the combination of anti-VEGF and cytotoxic therapy may maximize the efficacy of antineoplastic treatment regimens.