Involvement of nitric oxide in the inhibition of angiogenesis by interleukin‐2

Sakkoula, Eleni; Pipili-Synetos, Eva; Maragoudakis, Michael E.

doi:10.1038/sj.bjp.0701436

Cited by 40 publications

(27 citation statements)

References 11 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, tumor cell death caused by direct cell-to-cell contact with NK cells, macrophages, or other immune effector cells is unlikely. Indeed, recent evidence supports the occurrence of a local vascular leak syndrome provoked by lymphokines and nitric oxide produced by IL-2-activated immune effector cells (31,32). Furthermore, direct cytotoxic effects of IL-2 (12) and activated NK cells (33,34) on the endothelium were reported.…”

Section: Discussionmentioning

confidence: 97%

The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

Wagner

Schulz

Scholz

et al. 2008

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Effective control of pancreatic cancer has been hampered primarily by the lack of tumor specificity of current treatment modalities. The highly specific antibody-mediated delivery of therapeutic agents to the tumor microenvironment might overcome this problem. We therefore investigated the therapeutic efficacy of the targeted immunocytokine L19-Interleukin-2 (L19-IL2), consisting of the human single-chain Fv antibody L19, which is highly specific for the extradomain B (ED-B) of fibronectin, and the human cytokine IL-2, in pancreatic cancer. Experimental Design: Therapeutic effects of L19-IL-2, IL-2, and gemcitabine on tumor growth and metastasis were evaluated in orthotopic mouse models for pancreatic cancer. Immunohistochemistry was done to define ED-B expression, tumor necrosis, apoptosis, proliferation, and invasion of macrophages and natural killer (NK) cells. NK cells were depleted by i.v. injection of an anti-asialo-GM-1antibody. Results: ED-B is selectively expressed in human pancreatic cancer and in primary tumors and metastases of the mouse models. L19-IL-2 therapy was clearly superior to untargeted IL-2 or gemcitabine and inhibited tumor growth and metastasis with remarkable long-term tumor control. Therapeutic effects were associated with the induction of extensive tumor necrosis and inhibition of tumor cell proliferation. Immunohistochemistry revealed an increase of macrophages and NK cells in the tumor tissue, suggesting immune-mediated mechanisms. The functional relevance of NK cells for the therapeutic effect of the targeted immunocytokine L19-IL-2 was confirmed by NK cell depletion, which completely abolished its antitumor efficacy. Conclusions: These preclinical results strongly encourage the initiation of clinical studies using L19-IL-2 in pancreatic cancer.

show abstract

Section: Discussionmentioning

confidence: 97%

The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

Wagner

Schulz

Scholz

et al. 2008

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…These proteins can act as circulating hormones and/or as paracrine and autocrine factors, in various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, protease production, and apoptosis. Furthermore, the receptors for these hormones are members of the class 1 cytokine receptor superfamily, which also includes receptors for cytokines with recently discovered angiogenesisrelated effects, such as interleukin-2 (Sakkoula et al 1997, Johansson et al 2000), interleukin-15 (Angiolillo et al 1997, and erythropoietin (Yasuda et al 1998). In contrast to previously identified regulators of angiogenesis, the PRL/PL/GH family comprises homologous molecules that can either stimulate or inhibit the process (Fig.…”

Section: Discussionmentioning

confidence: 99%

Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis

Corbacho¹,

Escalera²,

Clapp³

2002

Journal of Endocrinology

233

149

View full text Add to dashboard Cite

Prolactin, growth hormone and placental lactogen are members of a family of polypeptide hormones which share structural similarities and biological activities. Numerous functions have been attributed to these hormones, among which stand out their recently discovered effects on angiogenesis, the process by which new blood vessels are formed from the pre-existing microvasculature. Prolactin, growth hormone and placental lactogen, along with two non-classical members of the family, proliferin and proliferin-related protein, can act both as circulating hormones and as paracrine/autocrine factors to either stimulate or inhibit various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, migration, protease production and apoptosis. Such opposing actions can reside in similar but independent molecules, as is the case of proliferin and proliferin-related protein, which stimulate and inhibit angiogenesis respectively. The potential to exert opposing effects on angiogenesis can also reside within the same molecule as the parent protein can promote angiogenesis (i.e. prolactin, growth hormone and placental lactogen), but after proteolytic processing the resulting peptide fragment acquires anti-angiogenic properties (i.e. 16 kDa prolactin, 16 kDa growth hormone and 16 kDa placental lactogen). The unique properties of the peptide fragments versus the full-length molecules, the regulation of the protease responsible for specific protein cleavage, the selective expression of specific receptors and their associated signal transduction pathways are issues that are being investigated to further establish the precise contribution of these hormones to angiogenesis under both physiological and pathological situations. In this review article, we summarize the known and speculative issues underlying the effects of the prolactin, growth hormone and placental lactogen family of proteins on angiogenesis, and address important remaining enigmas in this field of research.

show abstract

“…Additional studies indicated that NO donors reduced tissue angiogenesis and tumour neovascularization (Pipili-Synetos et al, 1995;Sakkoula et al, 1997). However, opinion on the role of NO in angiogenesis has been polarized by disparate observations in the literature.…”

Section: Introductionmentioning

confidence: 99%

Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival

Kane

Barker

Mitchell

et al. 2001

British J Pharmacology

View full text Add to dashboard Cite

1 We have examined the role of nitric oxide (NO) in a model of functional angiogenesis in which survival of a skin¯ap depends entirely on angiogenesis to provide an arterial blood supply to maintain tissue viability. 2 The dierent eects of nitric oxide synthase (NOS) inhibitors on rat skin¯ap survival appeared to be explained on the basis of their NOS isoform selectivity. Skin¯ap survival was decreased by iNOS-selective (inducible NOS) inhibitors, S-methyl-isothiourea, aminoguanidine and aminoethylthiorea; unaected by the non-selective inhibitor nitro-imino-L-ornithine; and enhanced by the cNOS (constitutive NOS, that is endothelial NOS (eNOS) and neuronal NOS (nNOS)) inhibitor, nitro-L-arginine methyl ester. 3 Skin¯ap survival was reduced in mice with targeted disruption of the iNOS gene (iNOS knockout mice), and the administration of nitro-L-arginine methyl ester signi®cantly increased¯ap survival in iNOS knockout mice (P50.05). 4 iNOS immunoreactivity was identi®ed in mast cells in the angiogenic region. Immunoreactive vascular endothelial growth factor (VEGF) and basic ®broblast growth factor were also localized to mast cells. 5 The combination of interferon-g and tumour necrosis factor-a induced NO production and increased VEGF levels in mast cells cultured from bone marrow of wild-type, but not iNOS KO mice. 6 The increased tissue survival associated with the capacity for iNOS expression may be related to iNOS-dependent enhancement of VEGF levels and an ensuing angiogenic response. Our results provide both pharmacological and genetic evidence that iNOS activity promotes survival of ischaemic tissue.

show abstract

Involvement of nitric oxide in the inhibition of angiogenesis by interleukin‐2

Cited by 40 publications

References 11 publications

The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

The Targeted Immunocytokine L19-IL2 Efficiently Inhibits the Growth of Orthotopic Pancreatic Cancer

Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis

Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival

Contact Info

Product

Resources

About