Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1658953 (tumor vasculature)
 2,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ED-B fibronectin (FN) is a FN isoform derived from alternative splicing of the primary transcript of a single gene. Its expression on tumor stroma and neoformed tumor vasculature and its absence, with few exceptions, in normal adult tissues imply a prognostic and diagnostic value for ED-B FN. We investigated the location and source of ED-B FN because this will be of importance both in understanding its role in tumor development and in designing strategies to target this molecule. We have confirmed that ED-B FN is expressed in the majority of breast and colorectal carcinoma tissue samples, with strong immunohistochemical staining around the tumor cells and in the tumor stroma. No staining of tumor neovasculature was seen. ED-B FN is produced by a range of tumor and endothelial (both primary and transformed) cell lines, as detected by reverse transcription-PCR, but is not expressed at the plasma membrane. Strong expression of human ED-B FN is seen in tumor xenografts. These data indicate that neoplastic cells can act as the source of ED-B FN in tumors. The lack of cell surface expression on tumor cell lines has clear implications for the design of therapeutic strategies which target this molecule.
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PMID:Source of oncofetal ED-B-containing fibronectin: implications of production by both tumor and endothelial cells. 1064 69

Angiogenic processes depend on the precise coordination of different cell types and a complex exchange of signals, many of which derive from new specific components of the provisional, angiogenesis-related, extracellular matrix (ECM). Angiogenesis-associated ECM components thus represent appealing targets for the selective delivery of therapeutic molecules to newly forming tumor vessels. Results of a previous study indicated that a high affinity recombinant antibody (L19) to ED-B, a domain contained in the angiogenesis-associated isoform of fibronectin (B-FN), selectively and efficiently targets tumor vessels. The present study shows that a fusion protein between L19 and interleukin 2 (L19-IL-2) mediates the selective delivery and concentration of IL-2 to tumor vasculature, thereby leading to a dramatic enhancement of the therapeutic properties of the cytokine. By contrast, IL-2 fused to an irrelevant recombinant antibody used as a control fusion protein showed neither accumulation in tumors nor therapeutic efficacy. Tumors in mice treated with L19-IL-2 were significantly smaller compared to those in animals treated with saline, the control fusion protein, or IL-2 alone (P =.003,.003, and.002, respectively). Moreover, no significant differences in size were observed among the tumors from the different control groups (using the control fusion protein, a mixture of IL-2 and L19, or saline alone). Immunohistochemical analysis of tumor infiltrates demonstrated a significantly higher number of T lymphocytes, natural killer cells, and macrophages, as well as increased interferon-gamma (IFN-gamma) accumulation, in tumors from animals treated with L19-IL-2 compared to tumors from control groups. The fact that ED-B is 100% homologous in human and mouse, thus ensuring that L19 reacts equally well with human and murine antigen, should ultimately expedite transfer of this reagent to clinical trials.
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PMID:Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix. 1186 Dec 59

A variety of therapeutic strategies in oncology are focused on the inhibition of tumor-induced angiogenesis. Thus, there is a keen interest in methods which allow non-invasive monitoring of molecular targets involved in angiogenesis which would support information for planning and controlling corresponding therapies. Moreover, such techniques would provide an insight into the formation of new sprouting blood vessels, the involved processes and regulatory mechanisms in patients. At the moment, development of radiotracer based techniques is mainly concentrated on three different targets which include peptidic and non-peptidic alpha v beta 3-integrin binding antagonists, matrix metalloproteinase inhibitors and single chain anti-fibronectin antibody fragments. Development of radiolabeled MMP inhibitors is based on either the decapeptide Cys-Thr-Thr-His-Trp-Gly-Phe-Thr-Leu-Cys resulting from a phage display library or small molecular weight compounds. The in vitro data for these tracers are very promising. However, more detailed in vivo data are necessary to evaluate the potency of MMP-inhibitors for in-vivo imaging. The radiolabelled anti-ED-B single chain antibody fragment scFv L-19 shows selective accumulation in the tumor vasculature in a murine tumour model. In a first patient study a selective localisation of the (123)I-labeled tracer in lesions of different tumours was found. On the basis of the lead structure cyclo(-Arg-Gly-Asp-dPhe-Val) a variety of different radiolabeled RGD-peptides has been developed for the non-invasive determination of the alpha v beta 3 expression. These developments include peptides labeled with minimum structural alteration, peptide carbohydrate conjugates, peptidomimetics based on the RGD-structure as well as heterodimeric, homodimeric and homotetrameric ligand systems. Many of the tracers show high alpha v beta 3-affinity and selectivity in vitro and receptor selective tumour accumulation with high image contrast in different murine tumour models. Further studies have to demonstrate that this approach can be translated to clinical settings allowing visualisation of alpha v beta 3-positive tumours and alpha v beta 3 expression during tumour-induced angiogenesis in patients.
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PMID:Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. 1513 68

IL-12 is a cytokine which showed anti-tumor effects in clinical trials, but also produced serious toxicity. We describe a fusion protein, huBC1-IL12, designed to achieve an improved therapeutic index by specifically targeting IL-12 to tumor and tumor vasculature. huBC-1 is a humanized antibody that targets a cryptic sequence of the human ED-B-containing fibronectin isoform, B-FN, present in the subendothelial extracellular matrix of most aggressive tumors. B-FN is oncofetal and angiogenesis-associated, and is undetectable in most normal adult tissues. The original murine BC-1 antibody has been used successfully for immunoscintigraphy to image brain tumor mass in glioblastoma patients. In huBC1-IL12, each of the IgG heavy chains is genetically fused to the N-terminus of the IL-12 p35 subunit, which in turn is disulfide-bonded to the p40 subunit, resulting in a hexameric molecule of MW of approximately 300 kDa. Since human IL-12 has no biological activity in mice, we produced huBC1-muIL12 as a surrogate molecule for animal tumor models. Despite the relatively poor PK profile of this molecule in mice and the apparent drawbacks of xenogeneic models in SCID mice, which lack T and B cells, one cycle of treatment with huBC1-muIL12 was efficacious in the PC3mm2, A431, and HT29 subcutaneous tumor models and PC3mm2 lung metastasis model. This molecule also was found to have surprisingly low toxicity in immunocompetent mice. A fusion protein that contains human IL-12 (huBC1-huIL12), which is a suitable molecule for investigation as a therapeutic, has also been produced. This protein has been shown to have a longer serum half-life than huBC1-muIL12 in mice, and retains both antigen binding and IL-12 activity in in vitro assays.
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PMID:huBC1-IL12, an immunocytokine which targets EDB-containing oncofetal fibronectin in tumors and tumor vasculature, shows potent anti-tumor activity in human tumor models. 1687 86

Photodynamic therapy (PDT) involves the combination of photosensitizers (PS) with light as a treatment, and has been an established medical practice for about 10 years. Current primary applications of PDT are age-related macular degeneration (AMD) and several types of cancer and precancer. Tumor vasculature and parenchyma cells are both potential targets of PDT damage. The preference of vascular versus cellular targeting is highly dependent upon the relative distribution of photosensitizers in each compartment, which is governed by the photosensitizer pharmacokinetic properties and can be effectively manipulated by the photosensitizer drug administration and light illumination interval (drug-light interval) during PDT treatment, or by the modification of photosensitizer molecular structure. PDT using shorter PS-light intervals mainly targets tumor vasculature by confining photosensitizer localization within blood vessels, whereas if the sensitizer has a reasonably long pharmacokinetic lifetime, then PDT at longer PS-light intervals can induce more tumor cellular damage, because the photosensitizer has then distributed into the tumor cellular compartment. This passive targeting mechanism is regulated by the innate photosensitizer physicochemical properties. In addition to the passive targeting approach, active targeting of various tumor endothelial and cellular markers has been studied extensively. The tumor cellular markers that have been explored for active photodynamic targeting are mainly tumor surface markers, including growth factor receptors, low-density lipoprotein (LDL) receptors, transferrin receptors, folic acid receptors, glucose transporters, integrin receptors, and insulin receptors. In addition to tumor surface proteins, nuclear receptors are targeted, as well. A limited number of studies have been performed to actively target tumor endothelial markers (ED-B domain of fibronectin, VEGF receptor-2, and neuropilin-1). Intracellular targeting is a challenge due to the difficulty in achieving sufficient penetration into the target cell, but significant progress has been made in this area. In this review, we summarize current studies of vascular and cellular targeting of PDT after more than 30 years of intensive efforts.
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PMID:Vascular and cellular targeting for photodynamic therapy. 1720 21

Treatment of tumor-bearing mice with mouse (m)TNF-alpha, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6 days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-alpha and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response.
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PMID:Therapy-induced antitumor vaccination by targeting tumor necrosis factor alpha to tumor vessels in combination with melphalan. 1802 63

Therapeutic vaccination targeting self-molecules is an attractive alternative to monoclonal antibody-based therapies for cancer and various inflammatory diseases. However, development of cancer vaccines targeting self-molecules has proven difficult. One complicating factor is that tumor cells have developed strategies to escape recognition by the immune system. Antigens specifically expressed by the tumor vasculature can therefore provide alternative targets. The alternatively spliced extra domain-A and B (ED-A and ED-B) of fibronectin are expressed during vasculogenesis in the embryo, but essentially undetectable under normal conditions in the adult. However, these domains are re-expressed during tumor angiogenesis and matrix remodeling, which renders them highly interesting for targeted cancer therapies. Using the MMTV-PyMT transgenic model of metastatic mammary carcinoma, we show that tumor burden can be significantly decreased by immunization against ED-A in a therapeutic setting. Furthermore, we found that in mice carrying anti-ED-A antibodies the number of metastases was reduced. ED-A immunization increased infiltration of macrophages and compromised tumor blood vessel function. These findings implicate an attack of the tumor vasculature by the immune system, through a polyclonal antibody response. We conclude that tumor vascular antigens are promising candidates for development of therapeutic vaccines targeting growth of primary tumors as well as disseminated disease.
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PMID:Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer. 2541 29