Angiogenesis as a target in neuroblastoma

Rößler, Jochen; Taylor, Mélissa; Geoerger, Birgit; Farace, Françoise; Lagodny, Jeanette; Peschka‐Süss, Regine; Niemeyer, Charlotte M.; Vassal, Gilles

doi:10.1016/j.ejca.2008.05.015

Cited by 58 publications

(60 citation statements)

References 91 publications

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“…Moreover, EZN-2208 exerted its superior potential in inhibiting tumor angiogenesis. Several recent studies implicate angiogenesis as an essential mechanism regulating neuroblastoma growth, and antiangiogenic therapies have been reviewed (42). The sprouting of new blood vessels from preexisting capillaries under the influence of proangiogenic growth factor expression, such as VEGF, has been reported (43).…”

Section: Discussionmentioning

confidence: 99%

Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Pastorino

Loi

Sapra

et al. 2010

Clinical Cancer Research

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Purpose: Treatment of neuroblastoma is successful in less than half of patients with high-risk disease. The antitumor activity of a water soluble pegylated SN38 drug conjugate, EZN-2208, was compared with CPT-11 (a prodrug for SN38) in preclinical models of human neuroblastoma.Experimental Design: The in vitro cytotoxicity of EZN-2208 was tested by counting trypan blue dyeand Annexin V-positive cells, whereas its therapeutic efficacy was evaluated, in terms of survival, and antitumor and antiangiogenic activities, in s.c. luciferase-transfected, pseudometastatic, and orthotopic neuroblastoma animal models.Results: EZN-2208 was about 100-fold more potent than CPT-11 in vitro, by inducing apoptosis/ necrosis and p53 expression and by reducing hypoxia-inducible factor (HIF)-1α/HIF-2α expression. EZN-2208 gave superior antitumor effects compared with CPT-11 in neuroblastoma xenografts. EZN-2208 treatment always resulted in lack of tumor detection at the end of trials whereas only small therapeutic effects were observed with CPT-11, as assessed by luciferase assay or tumor size, or even by staining histologic sections of tumors with antibodies recognizing neuroblastoma cells and cell proliferation. In a neuroblastoma model resistant to doxorubicin, cisplatin, vincristine, fenretinide, and topotecan, EZN-2208 induced 100% curability. It also blocked tumor relapse after topotecan-vincristine-doxorubicin combined treatment. Mechanistic experiments showed statistically significantly enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Histone H2ax staining as well as decreased vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, and MMP-9 expression in tumors removed from EZN-2208-treated mice and radiating vessels invading the tumor implanted onto the chorioallantoic membranes.Conclusions: EZN-2208 should be considered a most promising novel antineuroblastoma agent. An ongoing phase I study in pediatric patients should identify the optimal dose for a phase II study.

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Section: Discussionmentioning

confidence: 99%

Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Pastorino

Loi

Sapra

et al. 2010

Clinical Cancer Research

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“…Antiangiogenic approaches have become important therapeutic anticancer strategies (2). Important clues indicate that LXs, the first family of endogenous "braking signals" in inflammation identified in vivo (5), might interfere with tumor angiogenesis (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…The proangiogenic signals within tumors have been a focus of cancer research for several years, and targeting tumor vasculature represents a promising tool for cancer therapy (2).…”

Section: Introductionmentioning

confidence: 99%

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Chen

Hao

et al. 2010

Molecular Cancer Therapeutics

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Tumor angiogenesis plays an essential role in carcinogenesis, cancer progression, and metastasis. Some studies indicate that lipoxins, endogenous anti-inflammatory lipid mediators, might be involved in tumor angiogenesis; however, the governing mechanisms are still unknown. In the present study, we examined the effects of exogenous lipoxin A 4 (LXA 4 ) in mouse hepatocarcinoma cell line (H22) and H22-bearing mice model. It was found that in H22 cells, LXA 4 inhibited the production of vascular endothelial growth factor and reduced hypoxia-inducible factor-1α level. In addition, its analogue, BML-111, blocked the expression of vascular endothelial growth factor in serum and tumor sections from H22-bearing mice. H&E staining and immunostaining with antibodies against CD34 revealed that BML-111 suppressed tumor-related angiogenesis in vivo, but LXA 4 could not influence the proliferation of primary cultured human umbilical vein endothelial cells. The tumor growth was also inhibited by BML-111. We also found that BML-111 enhanced the in situ apoptosis while inhibiting macrophage infiltration in tumor tissue. The results provide new evidence that LXA 4 suppresses the growth of transplanted H22 tumor in mice through inhibiting tumor-related angiogenesis. Mol Cancer Ther; 9(8); 2164-74. ©2010 AACR.

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“…It has a broad spectrum of clinical behavior, which can range from spontaneous regression to dissemination and death (Rössler et al, 2008). Treatment and survival for children with NB has been greatly advanced by multimodal treatment protocols driven by collaborative groups such as the Children's Oncology Group.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma

Swenson

Harel

et al. 2015

J Pharmacol Exp Ther

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The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P 1-5 ) play critical roles in many pathologic processes, including cancer. The S1P axis has become a bona fide therapeutic target in cancer. , a known S1P 2 antagonist, suffers from instability in vivo. Structurally modified, more potent, and stable S1P 2 inhibitors would be desirable pharmacological tools. One of the JTE-013 derivatives,, exhibited improved S1P 2 antagonism compared with JTE-013. Intravenous pharmacokinetics indicated enhanced stability or slower clearance of AB1 in vivo. Migration assays in glioblastoma showed that AB1 was slightly more effective than JTE-013 in blocking S1P 2 -mediated inhibition of cell migration. Functional studies in the neuroblastoma (NB) cell line SK-N-AS showed that AB1 displayed potency at least equivalent to JTE-013 in affecting signaling molecules downstream of S1P 2 . Similarly, AB1 inhibition of the growth of SK-N-AS tumor xenografts was improved compared with JTE-013. Cell viability assays excluded that this enhanced AB1 effect is caused by inhibition of cancer cell survival. Both JTE-013 and AB1 trended to inhibit (C-C motif) ligand 2 expression and were able to significantly inhibit subsequent tumor-associated macrophage infiltration in NB xenografts. Interestingly, AB1 was more effective than JTE-013 in inhibiting the expression of the profibrotic mediator connective tissue growth factor. The terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling assay and cleaved caspase-3 detection further demonstrated that apoptosis was increased in AB1-treated NB xenografts compared with JTE-013. Overall, the modification of JTE-013 to produce the AB1 compound improved potency, intravenous pharmacokinetics, cellular activity, and antitumor activity in NB and may have enhanced clinical and experimental applicability.

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Angiogenesis as a target in neuroblastoma

Cited by 58 publications

References 91 publications

Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Tumor Regression and Curability of Preclinical Neuroblastoma Models by PEGylated SN38 (EZN-2208), a Novel Topoisomerase I Inhibitor

Lipoxin A4 and Its Analogue Suppress the Tumor Growth of Transplanted H22 in Mice: The Role of Antiangiogenesis

Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma

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