Effects Of Angiogenesis Inhibitors Research Articles

Effect of angiogenesis inhibitors on wound healing in patients with ovarian cancer: A meta-analysis.

Angiogenic inhibitors have been demonstrated to inhibit tumour cells in ovarian carcinoma, but the initial data are not accurate enough to indicate the influence of these drugs on the post-therapy wound healing. In order to assess the effect of angiogenic inhibitors on the treatment of wound healing in ovarian carcinoma, we performed a meta-analysis of related literature. For this meta-analysis, we looked up the data from 4 databases: PubMed, EMBASE, Web of Science and the Cochrane Library. All literature searches were performed up to October 2023. The ROBINS-I tool was applied to evaluate the risk of bias in the inclusion trials, and statistical analysis was performed with RevMan 5.3. In this research, 971 related research were chosen, and 9 of them were selected. These studies were published between 2013 and 2023. In all 9 trials, a total of 3902 patients were enrolled. There was a significant reduction in the risk of wound infection in the control group than in those who received angiogenesis inhibitors (OR, 0.66; 95% CI, 0.49-0.89 p = 0.007). The risk of developing an abscess was not significantly different from that of those who received angiogenesis inhibitors (OR, 0.80; 95% CI, 0.20-3.12 p = 0.74). The risk of perforation in the control group was smaller than that in those receiving angiogenic inhibitors (OR, 0.25; 95% CI, 0.11-0.56 p = 0.0006). There was a significant increase in the risk of injury and GI perforation in women who received angiogenic inhibitors than in the control group. But the incidence of abscess did not differ significantly among the two groups.

240 A Tardy Effect of Angiogenesis Inhibitors Leading to Accelerated Kidney Failure

240 A Tardy Effect of Angiogenesis Inhibitors Leading to Accelerated Kidney Failure

Combination therapy in cancer: effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics.

Validated preclinical studies have provided evidence that anti-vascular endothelial growth factor (VEGF) compounds enhance the activity of subsequent antitumor therapy, but the mechanism of this potentiation is far from clear. The most widespread explanation is enhanced delivery of therapeutics due to vascular remodeling, lower interstitial pressure, and increased blood flow. While the antiangiogenic effects on vascular morphology have been fairly consistent in both preclinical and clinical settings, the improvement of tumor vessel function is debated. This review focuses on the effect of anti-VEGF therapy on tumor microenvironment morphology and functions, and its therapeutic benefits when combined with other therapies. The uptake and spatial distribution of chemotherapeutic agents into the tumor after anti-VEGF are examined.

Angiogenesis inhibitors for patients with ovarian cancer: a meta-analysis of 12 randomized controlled trials

Objectives:To investigate the effects of angiogenesis inhibitors in the treatment of patients with advanced or recurrent ovarian cancer, a meta-analysis was performed and overall survival (OS), progression-free survival (PFS), and toxicity were assessed.Patients and methods:The PubMed and Embase databases, and the Cochrane Central Register of Controlled Trials were searched for publications between January 2000 and June 2015. Hazard ratios (HRs) with their 95% confidence intervals (CIs), or data for calculating HRs with 95% CIs were derived.Results:The 12 trials in this meta-analysis were divided into three groups: four trials with a VEGF inhibitor (the bevacizumab group), six trials with VEGFR inhibitors (the VEGFRIs group), and two trials with an angiopoietin inhibitor (the trebananib group). PFS improvement was seen in all groups (HR = 0.61, 95% CI 0.48 to 0.79, P < 0.001 for bevacizumab; HR = 0.71, 95% CI 0.59 to 0.87, P = 0.001 for VEGFRIs; and HR = 0.67, 95% CI 0.62 to 0.72, P < 0.001 for trebananib). Regarding OS, bevacizumab showed a trend of improvement (HR = 0.90, 95% CI 0.80 to 1.01, P = 0.079), VEGFRIs showed no improvement (HR = 0.92, 95% CI 0.75 to 1.11, P = 0.368), and trebananib demonstrated a significant prolongation (HR = 0.81, 95% CI 0.67 to 0.99, P = 0.036). Bevacizumab was associated with more class-specific adverse events (RR = 4.05, 95% CI 1.99 to 8.27, P < 0.001). Although the toxicity profiles differed, VEGFRIs developed common higher incidences of hypertension, diarrhea, and fatigue. A higher incidence of edema was reported in the trebananib group (RR = 2.60, 95% CI 0.84 to 8.00, P = 0.097).Conclusions:Anti-angiogenic therapy showed clear PFS benefit with increased toxicity, but its role in OS was undefined for ovarian cancer which emphasized the need for patient selection.

Abstract 1693: Bevacizumab acutely decreases endothelium dependent vasodilation in healthy volunteers

Abstract Introduction: Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. One of the most reported side effects of angiogenesis inhibitors is hypertension. In patients treated with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), hypertension has an overall incidence up to 32%. Understanding the pathogenesis of this side effect is essential for optimal treatment with this class of drugs. Microvascular endothelial dysfunction is involved in the pathogenesis of hypertension. Our hypothesis is that bevacizumab (BVZ) induced hypertension is caused by an acute reduction of endothelium-mediated vasodilation. Methods: BVZ was infused intra-arterially to separate direct local effects of VEGF inhibition from systemic actions, such as hypertension, that could indirectly interfere with endothelial function. At first, in seven volunteers the acute vasomotor effect of BVZ was studied. During 15 minutes BVZ 144 μg/dl forearm volume/min was infused in the brachial artery of the non-dominant arm while assessing forearm blood flow (FBF) with venous strain gauge plethysmography. During BVZ infusion venous blood was collected from both arms to measure local and systemic concentrations of BVZ. Subsequently the acute vasodilator response to intra-arterial acetylcholine (Ach, endothelium-dependent vasodilator) alone and during simultaneous infusion of BVZ was studied, in another group of 12 volunteers. Finally, the effect of BVZ on the response to an endothelium-independent vasodilator nitroprusside (SNP) was studied in a similar experimental set up, in a third group of 12 volunteers. Results: In the experimental arm during infusion BVZ reached a concentration of 135±10,7μg/ml (± SD; n=8), resembling systemic exposure to BVZ in patients treated with 5mg BVZ i.v./kg. BVZ concentration in the control arm was 6,7±1,1 μg/ml (n=10). Intra-arterial BVZ did not directly alter forearm vascular tone. Infusion of BVZ significantly reduced the percentage increase in forearm blood flow during infusion of two dosages of acetylcholine from (mean±SE) 440±157 and 926±252 to 169±154 and 612±40 (p&amp;lt;0,05, ANOVA for repeated measures on log-transformed data). In the absence of BVZ, the vasodilator response to SNP equaled the response to ACh. BVZ did not alter the percentage increase in forearm blood flow during infusion of SNP (n=12). Conclusion: Although BVZ did not alter baseline forearm vascular tone, it acutely and specifially reduced endothelium-mediated vasodilation. Although this observation suggests a minor role for the muscle vascular bed, a similar acute effect in other organs such as the kidney could very well be involved in the pathogenesis of BVZ-induced hypertension. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1693. doi:1538-7445.AM2012-1693

The effect of angiogenesis inhibitors in the treatment of malignant blood disorders

Le role de l’angiogenese est reconnu comme important dans les tumeurs solides, et ce n’est que recemment que les memes phenomenes ont ete decrits dans les hemopathies malignes. L’expression des peptides angiogeniques comme le vascular endothelial growth factor (VEGF) et le basic fibroblast growth factor (bFGF) est correlee avec la presentation clinique des lymphomes non hodgkiniens a grandes cellules. La densite en microvaisseaux dans le myelome multiple est un marqueur independant de survie. Tous ces resultats ont encourage le developpement de medicaments bloquant de maniere large les cytokines proangiogeniques, comme le lenalidomide, mais aussi d’agents cibles anti-VEGF. Cette revue reprend les connaissances sur l’angiogenese qui permettent de nouvelles ouvertures sur la physiologie et le traitement des hemopathies malignes. La problematique est maintenant de combiner les chimiotherapies avec ces nouvelles molecules pour obtenir lesmeilleurs resultats possibles et de les positionner par rapport a la greffe de moelle.

Etiology of OHSS and use of dopamine agonists

Vascular endothelial growth factor is the factor that causes increased capillary permeability and therefore the most serious manifestations of ovarian hyperstimulation syndrome. Dopamine agonists can both prevent and treat ovarian hyperstimulation syndrome by blocking expression of the vascular endothelial growth factor receptor.

Hypertension (HTN) in National Cancer Institute of Canada Clinical Trials Group study BR.24: A randomized, double-blind phase II trial of carboplatin (C) and paclitaxel (P) with either daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo, in patients with advanced non-small cell lung cancer

3527 Background: CED 30 mg/d with C+P increased response rate (RR: 38 vs 16% p &lt; 0.0001) and median progression free survival (PFS: 5.6 vs 5 m, hazard ratio [HR] 0.77) over C+P alone. HTN is a known effect of angiogenesis inhibitors (AI). For BR.24, we describe the incidence of HTN, effects on drug delivery, predictors of its development/worsening, and assess the predictive effect of HTN on efficacy. Methods: Pts received C+P plus either placebo (n =146) or CED (n = 148). HTN as an adverse event (HTN AE: defined as either new onset HTN, or worsening grade HTN in a previously hypertensive pt), was managed with a protocol-defined algorithm. Exploratory analyses characterized the relationship between HTN AE and baseline characteristics and treatment arm. Kaplan Meier curves summarized time to event outcomes and Cox regression models with time dependent covariates correlated HTN AE to outcomes. Results: Rate of pts with a history of HTN were similar: CED 26 %, placebo 33 %. CED pts had significantly higher HTN AE (any: 38 vs 12%, p &lt; 0.0001; grade 3 or 4: 19 vs 2 %). With the treatment algorithm, HTN AE had minimal impact on drug delivery (1 pt interrupted C+P, 11 pts [3.7%] reduced /discontinued CED / placebo). Headache was the only other AE that correlated with HTN AE. Predictors of HTN AE included: CED arm (p &lt; 0.0001), good ECOG (p = 0.02), female (p = 0.006), history of HTN (p = 0.06). CED pts with HTN AE had significantly higher RR (51.8 vs 32.6%, p = 0.025) and PFS (8.5 vs 5.1 m; HR 0.45, 95% CI 0.29 to 0.72, p = 0.0007); similar but not significant findings were observed with placebo (RR 35.3 vs 17.2%, p= 0.098; PFS 5.6 vs 4.9 m; HR 0.84, 95 % CI 0.45–1.54); the interaction term by treatment arm was not significant. Conclusions: CED pts had greater HTN AE, but this did not impact drug delivery. Certain baseline characteristics predicted HTN AE in all pts. Unexpectedly, development of on-study HTN predicted improved outcome in all pts, although to a greater extent for those on CED. Additional evaluation of the role of HTN AE as a predictor of efficacy of both AI and cytotoxics is warranted. [Table: see text]

Morphological Studies of Pulmonary Arteriovenous Shunting in a Lamb Model of Superior Cavopulmonary Anastomosis

The formation of pulmonary arteriovenous malformations (PAVMs) is now well described following surgical connection of the superior vena cava to the pulmonary arteries. The behavior of PAVMs is as fascinating as their cause is elusive. These abnormal vascular connections produce intrapulmonary shunting. The resulting systemic hypoxemia can be both progressive and clinically significant. The incidence and clinical impact of PAVMs are increased in patients operated on at a young age and in those with heterotaxy syndrome (left isomerism/polysplenia). Although the exact causes of PAVMs are not known, they are clearly associated with anatomic configurations in which there is no direct passage of hepatic venous blood to the pulmonary arterial system. They develop whenever hepatic venous blood must first pass through the systemic circulation before reaching the pulmonary vascular bed. One of the most intriguing clinical characteristics of PAVMs is their regression following surgical redirection of hepatic venous blood to the pulmonary arterial system. Regression can occur after either a completion Fontan procedure or heart transplantation. The clinical importance of PAVMs has been limited by the widespread practice of limiting the length of time between a superior cavopulmonary anastomosis and a completion Fontan procedure. Progression to a Fontan procedure improves systemic oxygenation both by eliminating intracardiac right-to-left shunting and by causing regression of the PAVMs. Various imaging techniques have been used to demonstrate PAVMs after a superior cavopulmonary anastomosis. These techniques may be either direct, showing the PAVMs, or indirect, showing the shunt resulting from the PAVMs. The most sensitive techniques are indirect: radionuclide pulmonary perfusion scanning and contrast echocardiography. Using these indirect techniques for detection, intrapulmonary shunting is essentially universal after superior cavopulmonary anastomosis [14]. Direct imaging techniques include pulmonary angiography and histological examination. Histological study of an autopsy specimen from a patient who died due to severe PAVMs showed numerous abnormal, thin-walled vessels [1]. Histological examination of lung biopsies from patients with PAVMs have shown large, dilated blood vessels (‘‘lakes’’) as well as smaller, clustered vessels (‘‘chains’’) in the pulmonary parenchyma [2, 11]. Lung biopsies from patients with a superior cavopulmonary anastomosis, but without PAVMs, have shown increased microvessel density, which may precede the formation of the dilated vessels (lakes) seen in patients with PAVMs [11]. Given the vascular nature of PAVMs, research on the molecular mechanisms of PAVM formation has focused on factors involved in angiogenesis. To date, mechanistic research on humans has been limited. Lung biopsies of children after superior cavopulmonary anastomosis have shown alterations in the vascular endothelial growth factor (VEGF) pathway, with increased levels of both VEGF and its receptor [12]. More extensive work has been carried out in two animal models of superior cavopulmonary anastomosis. Duncan et al. [10] developed a rat model to study potential mediators. They demonstrated increased levels of VEGF messenger RNA as well as protein levels of other angiogenic factors in the lungs of rats after superior cavopulmonary anastomosis [9, 13]. Although technically challenging, this small animal model may prove particularly useful in elucidating molecular mechanisms and testing the effects of angiogenesis inhibitors. S. M. Bradley (&) Pediatric Cardiac Surgery, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA e-mail: bradlesm@musc.edu

Effect of angiogenesis inhibitors on renal cell carcinoma

Sporadic renal cell carcinomas are characterized by EGFR (HER-1) and EGFR-2 (HER-2) expression, however, signal transduction inhibitors of this pathway were clinically ineffective. Clear cell renal cell cancer is hormone-, irradiation- and chemotherapy resistant with moderate sensitivity to immunotherapy. The only clinically effective class of agents in case of this tumor type was proved to be the angiosuppressive agents. In 2005 FDA approved sorafenib for the first line treatment while in 2006 sunitinib for second line treatment in the cytokine resistant medium-risk renal cell carcinoma. This was followed by the European approval of both agents for second line treatment of renal cell cancer. Sunitinib was approved for first line treatment of renal cell cancer in Europe based on a phase III trial comparing it to interferon. Temsirolimus obtained its approval for the treatment of high risk renal cell cancer patients in 2007. Last but not least, FDA approval is on the way in case of bevacizumab as well to treat renal cell cancer. Based on the data demonstrated on the ASCO'2007, various modalities have to be developed for various stages of progression of clear cell renal cell cancer.

A Critical View of Molecularly Target Therapy for Digestive Endocrine Tumours

Enteropancreatic endocrine tumours (EP ETs) are relatively rare neoplasms constituting a heterogeneous nosological category. Most EP ETs present with metastatic disease, are well-differentiated and have a relatively slow growth-rate, with high percentage of stable disease and relative long survival. In those patients with progressive disease biotherapy and chemotherapy have relatively low response rates. In this context, novel therapies are needed, especially for the treatment of progressive, metastatic disease which represents, in this field, the main therapeutic challenge. EP ETs seem an appropriate model for targeting angiogenesis, with solid data from animal and in vitro models. Effects of angiogenesis inhibitors, such as bevacizumab, sunitinib, thalidomide and endostatin seem promising especially in patients with pancreatic tumours. Targeting other tyrosine kinases such as EGFR (with gefitinib) or c-KIT (imatinib) has also been tested, with various degree of response. The mTOR pathway also looks as an interesting pathway to be targeted, with interesting data in some clinical trials. The main limits of the available data are represented by the high heterogeneity of patients and of inclusion criteria. Moreover, few studies included patients with documented progressive disease before treatment, thus making difficult to understand the real efficacy of treatment on spontaneous tumour growth. Future studies should evaluate combination therapies in more homogeneous populations of patients, and include clear definition of the individual progression rate before and after the study entry. An informative review of novel patents and therapeutic targets of enteropancreatic endocrine tumours are also discussed. Keywords: Gastroenteropancreatic endocrine tumours, carcinoids, novel therapeutic targets, angiogenesis, tyrosine kinase inhibitors, small molecules, VEGF, c-KIT, PDGFR, mTOR

Differential Effects of Vascular Endothelial Growth Factor Receptor-2 Inhibitor ZD6474 on Circulating Endothelial Progenitors and Mature Circulating Endothelial Cells: Implications for Use as a Surrogate Marker of Antiangiogenic Activity

Circulating endothelial cells (CEC) comprise at least two distinct populations: bone marrow-derived circulating endothelial progenitors (CEP) and mature CECs derived from existing vasculature. We hypothesized that antiangiogenic agents may have differential effects on CEPs and mature CECs and that these changes may serve as a marker of biological activity. The effect of angiogenesis inhibitors on CECs was evaluated by flow cytometry after vascular endothelial growth factor (VEGF)-induced mobilization and in mice bearing Lewis lung carcinoma (LLC). Tumor angiogenesis was evaluated in parallel by immunohistochemistry. In nontumor-bearing mice, VEGF administration increased both mature CECs and CEPs. This increase was inhibited by the VEGF receptor 2 inhibitor ZD6474 as well as the VEGF inhibitor-soluble Flt-1. ZD6474 had no significant effect on CECs in the absence of exogenous VEGF stimulation. In contrast, LLC-bearing mice had an increase in mature CECs but not CEPs after 3 days of treatment with ZD6474. The increase in mature CECs was dose-dependent, accompanied by a decrease in tumor microvessel density, and preceded reduction in tumor volume. Treatment of LLC-bearing mice with the vascular targeting agent ZD6126 also increased mature CECs. VEGF inhibitors can have differential effects on mature CECs and CEPs, and agents inhibiting tumor angiogenesis may cause a concomitant increase in mature CECs. This increase occurs in tumor-bearing but not in nontumor-bearing mice, suggesting that tumor endothelium is a potential source of mature CECs. Therefore, assessing both mature CECs and CEPs may provide insights into the mechanism of antiangiogenic agents and serve as an early surrogate marker of biological activity.

Levamisole Inhibits Angiogenesis in vitro and Tumor Growth in vivo

The synthetic anthelmintic compound Levamisole has previously been used in cancer treatment as an adjuvant in combination with 5-fluorouracil. Its mode of action remains unclear, but an immune-stimulatory effect has been suggested. Here, we show that Levamisole inhibits angiogenesis in vitro and tumor growth in vivo. In vitro, Levamisole specifically inhibits proliferation and differentiation of endothelial cells propagated in co-culture with fibroblasts. In vivo, Levamisole inhibits the growth in nude mice of a transplanted human tumor. The use of nude mice as tumor hosts permits the discrimination between the angiogenesis inhibitory effect of Levamisole and its assumed immune-stimulatory effect. Our findings support a possible therapeutic effect of angiogenesis inhibitors in the treatment of cancer and call for further investigations of the mechanism(s) underlying the anti-angiogenic effect of Levamisole.

Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells.

Endothelial cells involved in vasculogenesis and angiogenesis are key targets in cancer therapy. Recent evidence suggests that tumor cells can express some genes typically expressed by endothelial cells and form extracellular matrix-rich tubular networks, phenomena known as vasculogenic mimicry. We examined the effects of three angiogenesis inhibitors (i.e., anginex, TNP-470, and endostatin) on vasculogenic mimicry in human melanoma MUM-2B and C8161 cells and compared them with their effects in human endothelial HMEC-1 and HUVEC cells. Anginex, TNP-470, and endostatin markedly inhibited vascular cord and tube formation by HMEC-1 and HUVEC cells in vitro, whereas tubular network formation by MUM-2B and C8161 cells was relatively unaffected. Endothelial cells expressed higher mRNA and protein levels for two putative endostatin receptors, alpha5 integrin and heparin sulfate proteoglycan 2, than melanoma cells, suggesting a mechanistic basis for the differential response of the two cell types to angiogenesis inhibitors. These findings may contribute to the development of new antivascular therapeutic agents that target both angiogenesis and tumor cell vasculogenic mimicry.

Effect of angiogenesis inhibitors on oestrogen-mediated endometrial endothelial cell proliferation in the ovariectomized mouse

Effect of angiogenesis inhibitors on oestrogen-mediated endometrial endothelial cell proliferation in the ovariectomized mouse

Effect of angiogenesis inhibitors on oestrogen-mediated endometrial endothelial cell proliferation in the ovariectomized mouse.

It has been suggested that endometrial angiogenesis in response to the sex steroids oestrogen and progesterone is mediated at a local level via compounds such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), acting through their respective tyrosine kinase receptors. The aim of the present study was to use SUGEN tyrosine kinase receptor angiogenic inhibitor compounds SU5416, SU5402, SU11652 and SU11685, to determine whether VEGF, FGF or PDGF play a role in mediating endometrial endothelial cell proliferation after administration of oestrogen and progesterone. Endometrial endothelial cell proliferation was induced in adult ovariectomized mice by either oestrogen alone for 24 h (E1), or a regimen using oestrogen alone, then progesterone with low dose oestrogen, followed by progesterone with high-dose oestrogen (PE) over a total of 7 days. Each angiogenesis inhibitor compound was injected daily for 4 days (100 mg kg(-1) day(-1), s.c.) before endometrial tissue collection at either the E1 or PE stage. This study also evaluated the effect of VEGF antiserum (0.2 ml, i.p.) on endothelial cell proliferation at the E1 stage. All four angiogenic inhibitor compounds significantly reduced endothelial cell proliferation activity at the E1 and PE stages. The greatest reduction in the endothelial cell proliferative index was at the E1 stage in the group treated with the VEGF receptor inhibitor SU5416 (2.5 +/- 0.7% versus 27.9 +/- 1.1%, P < 0.001), with a reduction of similar magnitude in the group treated with anti-VEGF antibody. At the PE stage, all four inhibitors significantly reduced endothelial cell proliferation to a similar extent, indicating that VEGF, FGF and PDGF are all involved. These results demonstrate that endometrial angiogenesis after acute oestrogen treatment is primarily mediated by VEGF, but that under the influence of combined oestrogen and progesterone, FGF and PDGF are also probably involved.

Noninvasive assessment of neoplastic angiogenesis: the role of magnetic resonance imaging.

The study of the effect of angiogenesis inhibitors on tumors is limited by our ability to assess their effect in vivo. Approaches that are currently employed have significant limitations. An ideal approach would employ a widely available noninvasive technology that can be used repeatedly to assess the antiangiogenic effect on the same lesions in a serial fashion. We describe here a specialized magnetic resonance imaging (MRI)-based technique that we employ in the study of angiogenesis of brain tumors. This technique, called relative cerebral blood volume (rCBV) mapping, is a noninvasive technique that adds just a few minutes to the conventional MRI study of a human brain tumor in the clinical setting. We hope that such a technique will serve as a model for developing new imaging techniques for the assessment of angiogenesis modulation in other tumor settings. We describe the technical basis and some examples of using rCBV mapping in neoplastic angiogenesis assessment, including a discussion of current limitations and future directions.

Tumor vascularity: evaluation in a murine model with contrast-enhanced color Doppler US effect of angiogenesis inhibitors.

To determine the ability of contrast material-enhanced ultrasonography (US) to depict tumor growth and vascularity in a murine model of prostate carcinoma treated with an angiogenic inhibitor. Thirty-five genetically engineered mice with spontaneously occurring prostate tumors were monitored on a weekly basis with gray-scale and color Doppler US with a 15-MHz linear transducer. Eighteen mice were treated with an adenoviral vector to deliver a soluble form of the Flk1 receptor (VEGFR-2), a vascular endothelial growth factor receptor designed to block tumor angiogenesis. The remaining 17 animals were injected with saline and used as controls. Tumor volumes were calculated on the basis of serial US measurements. Color Doppler US was performed in every tumor before and after intravenous injection of 0.1 mL per kilogram of body weight of a US contrast agent. US images were evaluated for tumor size, pattern of vascularity, and extent of vascularity (vascularity index). Findings at US were correlated with findings at autopsy in 30 animals. Estimates of tumor volume at US correlated well with tumor measurements at autopsy (r =.89, P <.001). Marked differences in tumor size and slope of increasing tumor volume were evident at US between treated and control mice after treatment (P <.016, analysis of variance). The US contrast agent markedly increased color Doppler US signal intensity with an 800% (from 10% to 12,700%) change in the mean number of color pixels per imaging field, and showed vascularity in areas of tumor not identified on precontrast images in 70% (109 of 156 studies). No correlation was found between the pattern of vascularity or vascularity index before or after contrast material administration and tumor size, treatment status, or histologic assessment of tumor vascularity. Contrast-enhanced US improves visualization of tumor vascularity. However, histologic patterns of tumor vascularity do not correlate with Doppler US depiction of blood flow in these vessels.

Combined effects of angiogenesis inhibitors and radiation on human microvascular endothelial cells

Combined effects of angiogenesis inhibitors and radiation on human microvascular endothelial cells

Angiogenesis inhibitor TNP-470 suppresses the progression of experimentally-induced hepatocellular carcinoma in rats.

We evaluated the effects of angiogenesis inhibitor, TNP-470, on hepatocellular carcinoma (HCCs) induced by a choline-deficient L-amino acid defined (CDAA) diet in rats. Male Fisher 344 rats were fed CDAA for 68 weeks. Rats were treated by subcutaneous injection of TNP-470 (15 mg/kg) or saline (control) three times per week from 53 to 68 weeks. At the end of the experiment, we determined the frequency and size of HCCs and glutathione S-transferase placental form (GSTP)-positive lesions, histology of liver cirrhosis, liver function, and liver weight per body weight. We also determined, using histologic and immunohistochemical semiquantification analyses, the degree of vascularity, apoptosis and proliferation in HCC and adjacent tissues. Treatment with TNP-470 resulted in a reduction of the size and frequency of HCC compared to untreated rats. However, TNP-470 did not influence the histology of liver cirrhosis and liver function. The liver weight per body weight of TNP-470-treated rats was slightly heavier in comparison with that of the controls. Treatment with TNP-470 significantly reduced tumor vascularity relative to the controls. There were no significant differences in the Ki-67 labeling index of HCCs between TNP-470 treated and control rats. The frequency of apoptotic hepatoma cells in TNP-470-treated rats was higher than in control rats. Our results indicate that TNP-470 suppresses the progression of CDAA-induced HCCs in rats through inhibition of angiogenesis, and suggest that TNP-470 might be useful clinically for HCCs.