Phase I trial of metronomic oral vinorelbine in patients with advanced cancer

Background  

Antitubulin agents exhibit antiangiogenic effects in vitro and in vivo. We evaluated the safety and feasibility of administering a metronomic schedule of oral vinorelbine designed to optimize its antiangiogenic effects.     

Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice

Purpose  

The natural flavonoid fisetin was recently identified as a lead compound that stabilizes endothelial cell microtubules. In this study, we investigated the antiproliferative and antiangiogenic properties of fisetin in vitro and in vivo.     

Vasohibin inhibits angiogenic sprouting in vitro and supports vascular maturation processes in vivo

Background  

The murine homologue of human vasohibin (mVASH1), a putative antiangiogenic protein, was investigated for its effects on in vitro and in vivo angiogenesis.     

Metronomic docetaxel chemotherapy inhibits angiogenesis and tumor growth in a gastric cancer model

Purpose  

Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and less side effects. The aim of the study is to rationally develop a docetaxel metronomic regimen in preclinical settings of gastric cancer.     

去甲苔藓葸噻吩抑制血管生成作用的体外实验研究

Objective  

The aim of the study was to investigate the effect of Demethyl bryoanthrathiophene (DBT) on proliferations of human umbilical vein endothelial cells (HUVECs) and human lung adenocarcinoma cell line A549, and antiangiogenic effect of DBT on HUVECs in vitro.     

Inhibition of angiogenesis and suppression of colorectal cancer metastatic to the liver using the <Emphasis Type="Italic">Sleeping Beauty</Emphasis> Transposon System

Background  

Metastatic colon cancer is one of the leading causes of cancer-related death worldwide, with disease progression and metastatic spread being closely associated with angiogenesis. We investigated whether an antiangiogenic gene transfer approach using the Sleeping Beauty (SB) transposon system could be used to inhibit growth of colorectal tumors metastatic to the liver.     

Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer

Background  

Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing.     

Association of interleukin-10 gene haplotype with gastric cancer in a Chinese population

Objective  

Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and antiangiogenic functions. Previous studies have reported that IL-10 levels are significantly elevated in patients with gastric cancer (GC). It has also been confirmed that interindividual variations in IL-10 production are genetically attributed to the polymorphisms of IL-10 gene. Therefore, this study was designed to investigate whether the polymorphisms of IL-10 gene were associated with susceptibility to GC in the Chinese population.     

Anti-vascular endothelial growth factor therapy in the era of personalized medicine

Purpose

To review key clinical issues underlying the assessment of in vivo efficacy when using antiangiogenic therapies for cancer treatment.

Methods

Literature relevant to use of antiangiogenic therapies in cancer was reviewed, with particular emphasis on the assessment of in vivo efficacy of these agents, as well as additional angiogenic factors that could play a role in escape from angiogenesis inhibition.

Results

In order to grow and metastasize, tumors need to continually acquire new blood supplies; therefore, therapeutic inhibition of angiogenesis has become a component of anticancer treatment for many tumor types. Bevacizumab, a humanized monoclonal antibody directed at vascular endothelial growth factor A (VEGF-A), has shown activity in combination with chemotherapy in metastatic colorectal cancer. Nevertheless, the use of antiangiogenic therapies remains suboptimal; specifically, optimal dose, duration of therapy, and combination of agents remain unknown. Also, at present, it is not possible to determine which patients are most likely to respond to a given form of antiangiogenic therapy. There has been increased recognition of alternative pathways possibly associated with disease progression in patients undergoing antiangiogenic therapy targeted at VEGF-A. Multiligand-targeted antiangiogenic therapies, such as ziv-aflibercept (formerly known as aflibercept, VEGF Trap), are currently undergoing clinical evaluation. Ziv-aflibercept forms monomeric complexes with VEGF-A, VEGF-B, and PlGF, which have a long half-life, allowing optimization of ziv-aflibercept doses and angiogenic blockage.

Conclusions

Although antiangiogenic therapies have increased treatment options for cancer patients, their use is limited by a lack of established and standardized methodology to evaluate their efficacy in vivo. Circulating endothelial cells, hypertension, and several molecular and imaging-based markers have potential for use as biomarkers in these patients and may better define appropriate patient populations.     

Angiogenesis and lymphangiogenesis are downregulated in primary breast cancer

Background:

Angiogenesis and lymphangiogenesis are considered to play key roles in tumour growth, progression and metastasis. However, targeting tumour angiogenesis in clinical trials showed only modest efficacy. We therefore scrutinised the concept of tumour angiogenesis and lymphangiogenesis by analysing the expression of crucial markers involved in these processes in primary breast cancer.

Methods:

We analysed the expression of angiogenic, lymphangiogenic or antiangiogenic factors, their respective receptors and specific markers for endothelial and lymphendothelial cells by quantitative real-time RT-PCR in primary breast cancer and compared the expression profiles to non-cancerous, tumour-adjacent tissues and breast tissues from healthy women.

Results:

We found decreased mRNA amounts of major angiogenic and lymphangiogenic factors in tumour compared to healthy tissues, whereas antiangiogenic factors were upregulated. Concomitantly, angiogenic and lymphangiogenic receptors were downregulated in breast tumours. This antiangiogenic, antilymphangiogenic microenvironment was even more pronounced in aggressive tumours and accompanied by reduced amounts of endothelial and lymphatic endothelial cell markers.

Conclusion:

Primary breast tumours are not a site of highly active angiogenesis and lymphangiogenesis. Selection for tumour cells that survive with minimal vascular supply may account for this observation in clinical apparent tumours.     

uPA is upregulated by high dose celecoxib in women at increased risk of developing breast cancer

Background  

While increased urokinase-type plasminogen activator (uPA) expression in breast cancer tissue is directly associated with poor prognosis, recent evidence suggests that uPA overexpression may suppress tumor growth and prolong survival. Celecoxib has been shown to have antiangiogenic and antiproliferative properties. We sought to determine if uPA, PA inhibitor (PAI)-1 and prostaglandin (PG)E₂ expression in nipple aspirate fluid (NAF) and uPA and PGE₂ expression in plasma were altered by celecoxib dose and concentration in women at increased breast cancer risk.     

Near-infrared optical imaging of cancer vascular remodeling after antiangiogenic therapy

Background

Near-infrared diffuse optical imaging (DOSI) has been recently accepted as a method to assess tumor vascularity and oxygenation by measuring tissue hemoglobin (Hb) concentration. It is expected that DOSI could be used to monitor changes in vascularity after antiangiogenic therapy.

Methods

A patient with advanced breast cancer was treated with single-agent bevacizumab followed by addition of weekly paclitaxel to it. DOSI was performed in the tumor-bearing breast and contralateral normal breast at baseline, 3, 6, 12, 24 h, and then daily for 1 week. Images of a tumor-to-normal ratio of tHb (rtHb) were constructed for identifying a tumor lesion.

Results

Serial images of rtHb showed a tumor lesion which corresponded to a hot spot. The level of rtHb rapidly decreased within several hours after administration of single-agent bevacizumab and then persisted at low levels during treatment. From day 2, the value of rtHb gradually increased and peaked on day 5.

Conclusion

This trend may be explained considering sequential images of rtHb indicating the inhibition of angiogenesis due to antiangiogenic therapy. We conducted a clinical study using single-agent bevacizumab followed by neoadjuvant chemotherapy in primary breast cancer patients to understand vascular remodeling after antiangiogenic agent at very early time points using DOSI.     

Combining Bevacizumab with Temozolomide Increases the Antitumor Efficacy of Temozolomide in a Human Glioblastoma Orthotopic Xenograft Model

Purpose

The aims of the present work were to investigate the in vitro and in vivo antiangiogenic effects of chronic temozolomide treatment on various glioma models and to demonstrate whether bevacizumab (Avastin) increased the therapeutic benefits contributed by temozolomide in glioma.

Experimental Design

The expression levels of various antiangiogenic factors in four glioma cell lines were evaluated after chronic in vitro treatment with temozolomide by Western blot. Proliferation and migration assays were performed on human endothelial cells incubated with supernatants of glioma cells treated with and without temozolomide. Orthotopic glioma models were used to evaluate the antiangiogenic effects of temozolomide in vivo and the therapeutic benefits of different temozolomide treatment schedules used alone or in combination with bevacizumab.

Results

Temozolomide, a proautophagic and proapoptotic drug, decreased the expression levels of HIF-1α, ID-1, ID-2, and cMyc in the glioma models investigated, all of which playing major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be, at least partly, responsible for the impairment of angiogenesis observed in vitro and in vivo. Moreover, combining bevacizumab with temozolomide increased the survival of glioma-bearing mice in comparison to each compound administered alone.

Conclusions

In addition to the numerous mechanisms of action already identified for temozolomide, we report here that it also exerts antitumor effects by impairing angiogenic processes. We further emphasize that bevacizumab, which is an antiangiogenic drug with a different mechanism of action, could be useful in combination with temozolomide to increase the latter''s therapeutic benefit in glioma patients.     

Actualités thérapeutiques dans le cancer du rein métastatique

Introduction

For some years, therapeutic management of metastatic renal cancers benefits from considerable progress.

Point

Define the efficiency of antiangiogenic molecules and the new recommendations of the treatment of metastatic renal cancer.

Material and methods

An English bibliographical search was realized from the data bank Medline (PubMed) using the following keywords: renal cell carcinoma, immunotherapy, antiangiogenic drugs, and tyrosine kinase inhibitors, and about 20 published articles were consulted including phases II and III randomized trials.

Results

Since 2004, the treatment ofmetastatic renal cancer is constantly changing. Before, the treatment was based essentially on the use of cytokines determining the era of the immunotherapy. At present, the studies of the tumoral biology as well as the genetic aspects of the pathology showed the utility of new molecules with the antiangiogenic properties, which were able to define new therapeutic standards. The results of these targeted therapies concern especially the improvement of the progression-free survival with the sunitinib or the bevacizumab used in the first line of treatment, or with the sorafenib used in second line. The inhibitors of m-TOR (temsirolimus) can be usedwith a benefit on the overall survival in the cases of metastatic renal cancers with bad prognosis.

Conclusion

In spite of the current therapeutic progress, the prognosis of metastatic renal cancer is still bad. Consequently, it is important to intensify the researches and to follow any therapeutic development.     

Halofuginone inhibits phosphorylation of SMAD-2 reducing angiogenesis and leukemia burden in an acute promyelocytic leukemia mouse model

Background

Halofuginone (HF) is a low-molecular-weight alkaloid that has been demonstrated to interfere with Metalloproteinase-2 (MMP-2) and Tumor Growth Factor-β (TGF-β) function and, to present antiangiogenic, antiproliferative and proapoptotic properties in several solid tumor models. Based on the fact that high levels of Vascular Endothelial Growth Factor (VEGF) and increased angiogenesis have been described in acute myeloid leukemia and associated with disease progression, we studied the in vivo effects of HF using an Acute Promyelocytic Leukemia (APL) mouse model.

Methods

NOD/SCID mice were transplanted with leukemic cells from hCG-PML/RARA transgenic mice (TM) and treated with HF 150 μg/kg/day for 21 days. The leukemic infiltration and the percentage of VEGF+ cells were evaluated by morphology and flow cytometry. The effect of HF on the gene expression of several pro- and antiangiogenic factors, phosphorylation of SMAD2 and VEGF secretion was assessed in vitro using NB4 and HUVEC cells.

Results

HF treatment resulted in hematological remission with decreased accumulation of immature cell and lower amounts of VEGF in BM of leukemic mice. In vitro, HF modulated gene expression of several pro- and antiangiogenic factors, reduced VEGF secretion and phosphorylation of SMAD2, blocking TGF-β-signaling.

Conclusion

Taken together, our results demonstrate that HF inhibits SMAD2 signaling and reduces leukemia growth and angiogenesis.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-015-0181-2) contains supplementary material, which is available to authorized users.     

Toll-like receptor 9 agonist IMO cooperates with everolimus in renal cell carcinoma by interfering with tumour growth and angiogenesis

Background:

Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors.

Methods:

We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells.

Results:

Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions.

Conclusion:

A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting.     

Early alpha‐fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma

BACKGROUND:

Antiangiogenic therapy has become the most important treatment modality for patients with advanced hepatocellular carcinoma (HCC). In this study, the authors investigated levels of alpha‐fetoprotein (AFP) as a potential biomarker for treatment efficacy of antiangiogenic therapy.

METHODS:

Patients with advanced HCC who had been enrolled in 3 prospective phase 2 clinical trials that evaluated either sorafenib, bevacizumab, or thalidomide in combination with a potentially antiangiogenic, metronomic, oral 5‐fluoropyrimidine as first‐line systemic therapy were included. An early AFP response was defined as a decline >20% from baseline after 2 to 4 weeks of treatment. AFP response was analyzed for its association with treatment efficacy and survival outcome.

RESULTS:

Seventy‐two patients were included for early AFP response evaluation, and 12 of those patients (17%) were classified as early AFP responders. Early AFP responders, compared with nonresponders, had a significantly improved overall response rate (33% vs 8%; P = .037) and a significantly improved disease control rate (83% vs 35%; P = .002), which was defined as the percentage of patients who had an objective response plus stable disease for a minimum of 8 weeks. AFP responders, compared with nonresponders, also had longer median progression‐free survival (PFS) (7.5 months vs 1.9 months; P = .001) and longer median overall survival (OS) (15.3 months vs 4.1 months; P = .019). In a multivariate analysis, AFP response remained a significant independent predictor of better PFS and OS.

CONCLUSIONS:

The current results indicated that an early AFP response is a useful surrogate marker to predict treatment response and prognosis in patients with advanced HCC who receive antiangiogenic therapy. Cancer 2010. © 2010 American Cancer Society.     

Effects of tyrosine kinase inhibitor E7080 and eNOS inhibitor L-NIO on colorectal cancer alone and in combination

Objective：To investigate the effects of E7080 and N5-（1-iminoethyl）-L-ornithine dihydrochloride （L-NIO）on colorectal cancer alone and in combination.Methods：HT29 colorectal cancer cell line from Sap Institute was used.Real-time cell analysis （xCELLigence system） was performed to determine the effects of E7080 and L-NIO on colorectal cell proliferation.While apoptosis was determined with Annexin V staining,and the effect of agents on angiogenesis was determined with chorioallantoic membrane （CAM） model.Results：We found that E7080 has a strong antiproliferative effect with an half maximum inhibition of concentration （IC50） value of 5.60×10-8 mol/L.Also it has been observed that E7080 showed antiangiogenic and apoptotic effects on HT29 colorectal cancer cells.Antiangiogenic scores of E7080 were 1.2,t.0 and 0.6 for 100,10 and 1 nmol/L E7080 concentrations,respectively.Furthermore,apoptosis has been detected in 71％ of HT29 colorectal cancer cells after administration of 100 nmol/L E7080 which may indicate strong apoptotic effect.Meanwhile administration of L-NIO alone did not show any effect,but the combination of E7080 with L-NIO increased the antiproliferative,antiangiogenic and apoptotic effects of E7080.Conclusions：Results of this study indicate that E7080 may be a good choice in treatment of colorectal tumors.Furthermore the increased effects of E7080 when combined with L-NIO raise the possibility to use a lower dose of E7080 and therefore avoid/minimize the side effects observed with E7080.