Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumoral angiogenesis is necessary for the growth of neoplasms and the production of metastasis. The vascular endothelial growth factor (VEGF) is a homodimeric heparin-binding glycoprotein that binds to VEGF-receptors and can induce endothelial cell mitosis, invasion, and eventually capillary tube formation. Bevacizumab, a humanized monoclonal antibody against VEGF, inhibits tumoral angiogenesis and may also improve the delivery of chemotherapy to the tumor mass. Some new antiangiogenic agents, called multi-kinase inhibitors (sorafenib and sunitinib), have also activity against other receptors, such as epidermal growth factor-receptor or platelet-derived growth factor-receptor. A new schedule of treatment (metronomic chemotherapy) also has antiangiogenic activity.
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PMID:Tumoral angiogenesis: review of the literature. 1818 Oct 52

Vascular endothelial growth factor (VEGF) produced by tumor cells plays a central role in stimulating angiogenesis required for solid tumor growth. VEGF-specific antibodies inhibit tumor cell line growth in animal models and a humanized monoclonal anti-VEGF antibody (bevacizumab [Avastin]) is approved as a treatment for metastatic cancer. We hypothesized that administration of an adenoviral (Ad) vector expressing the murine monoclonal antibody equivalent of bevacizumab would suppress human tumor growth in vivo. The Ad vector (AdalphaVEGF) encodes the light chain and heavy chain cDNAs of monoclonal antibody A.4.6.1, a murine antibody that specifically recognizes human VEGF with the same antigen-binding site as bevacizumab. AdalphaVEGF efficacy in vivo was evaluated with A-673 rhabdomyosarcoma and DU 145 prostate carcinoma cells in human tumor cell xenografts in SCID mice. For both tumor models, AdalphaVEGF directed the expression of high anti-human VEGF IgG antibody titers in vivo, the numbers of mitotic nuclei and blood vessels in the tumor were significantly decreased (p < 0.05), tumor growth was suppressed (p < 0.05), and there was increased survival (p < 0.005). Thus, AdalphaVEGF, encoding a murine monoclonal antibody that is the equivalent of bevacizumab, effectively suppresses the growth of human tumors, suggesting gene therapy as an alternative to bevacizumab monoclonal antibody therapy.
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PMID:Genetic delivery of the murine equivalent of bevacizumab (avastin), an anti-vascular endothelial growth factor monoclonal antibody, to suppress growth of human tumors in immunodeficient mice. 1832 12

Bevacizumab, an anti-vascular endothelial growth factor recombinant humanized monoclonal antibody, directly inhibits tumor angiogenesis and hence tumor growth. First-line therapy with intravenous bevacizumab 10 mg/kg every 2 weeks plus subcutaneous interferon-alpha-2a 9 million international units three times weekly has been evaluated in two randomized, double-blind or open-label, multicenter phase III trials (AVOREN [n = 649] and CALGB 90206 [n = 732]). Bevacizumab combination therapy resulted in a median progression-free survival that was significantly (p < or = 0.0001) longer than that seen with placebo plus interferon-[alpha]-2a in AVOREN (10.2 vs 5.4 months) [hazard ratio (HR) 0.63 (95% CI 0.52, 0.75)] and that seen with interferon-alpha-2a alone in CALGB 90206 (8.5 vs 5.2 months). Overall survival data in AVOREN and CALGB 90206 are not yet mature. In the interim overall survival analysis in AVOREN, median overall survival was 19.8 months with placebo plus interferon-alpha-2a, but had not yet been reached with bevacizumab plus interferon-alpha-2a (HR 0.79 [95% CI 0.62, 1.02; p = 0.0670]). The overall tumor response rate with bevacizumab plus interferon-alpha-2a was significantly (p < or = 0.0001) higher than with placebo plus interferon-alpha-2a in AVOREN (31% vs 13%) and that with interferon-alpha-2a alone in CALGB 90206 (25.5% vs 13.1%). Subgroup analyses in AVOREN suggested that interferon-alpha-2a dose reductions (to manage grade > or =3 adverse events attributable to the drug) did not compromise the efficacy of combination treatment with bevacizumab plus interferon-alpha-2a. The addition of bevacizumab to interferon-alpha-2a in AVOREN was generally well tolerated. No unexpected/new adverse events were observed; bevacizumab-associated toxicities were generally of mild intensity.
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PMID:Bevacizumab: in first-line treatment of advanced and/or metastatic renal cell carcinoma. 1834 8

Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy-namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4-Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.
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PMID:Drug insight: antiangiogenic therapies for gastrointestinal cancers--focus on monoclonal antibodies. 1838 35

Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP) regulate each other, contributing to tumor progression. We have previously reported that MMP9 induces the release of tumor VEGF, promoting ascites formation in human ovarian carcinoma xenografts. The aim of this study was to investigate whether tumor-derived VEGF regulated the expression of gelatinase by the stroma, influencing the invasive properties of ovarian tumors. Tumor variants derived from 1A9 human ovarian carcinoma, stably expressing VEGF(121) in the sense (1A9-VS-1) and antisense orientations (1A9-VAS-3), were used. In vivo, zymographic analysis of tumors from 1A9-VS-1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases, particularly murine MMP9, indicating that VEGF stimulates host expression of the matrix-degrading enzyme. Murine MMP9 expression was also high in the ovaries of mice bearing 1A9-VS-1 tumors. The effect on host MMP9 activity was organ-specific. The levels of host pro-MMP9 in ovaries correlated with the plasma levels of tumor VEGF and with the selective invasion of the ovaries. Induction of host MMP9 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice carrying both intraperitoneal and subcutaneous tumors. The anti-VEGF antibody bevacizumab (Avastin) inhibited MMP9 expression and tumor invasion in the ovaries of mice bearing 1A9-VS-1 tumors. These findings point to a complex cross-talk between VEGF and MMPs in the progression of ovarian tumor and suggest the possibility of using VEGF inhibitors to affect MMP-dependent tumor invasion.
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PMID:Vascular endothelial growth factor stimulates organ-specific host matrix metalloproteinase-9 expression and ovarian cancer invasion. 1840 33

Until recently, advances in non-small-cell lung cancer (NSCLC) care have been limited; new chemotherapy regimens have not significantly impacted patient survival. With our improved understanding of tumor biology, novel biological therapies targeting key tumorigenic processes targeting factors essential for tumor growth, such as angiogenesis, have been developed that improve patient outcomes beyond those achieved with chemotherapy alone. One of these, bevacizumab (Avastin), specifically targets VEGF, which is key to the malignant growth and progression of solid tumors. Bevacizumab-based therapy until progression significantly delays disease progression, has a well-characterized and acceptable safety profile in bevacizumab-eligible patients and was the first treatment to improve the overall survival of patients with advanced NSCLC beyond 1 year, a significant breakthrough in advanced NSCLC care. Furthermore, bevacizumab-based therapy significantly delays disease progression and has a well-characterized and acceptable safety profile. Based on these data, bevacizumab has received approval for the first-line treatment of NSCLC in the USA and Europe. A number of ongoing trials will potentially expand the eligible patient population for bevacizumab and further define its role in NSCLC treatment.
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PMID:Bevacizumab for the treatment of advanced non-small-cell lung cancer. 1847 Oct 42

Extensive research over the past two decades in tumor immunology has shown that immune reactivity to tumor antigens can restrict tumor growth and/or metastasis, especially when tumor burden is low. These observations in experimental models have been translated into clinical studies involving both active and passive forms of immunotherapies. While immune responses to specific tumor antigens can be detected in patients with various types of cancers, responses to any single antigen seldom correlate directly with a clinical response to tumors; however, some clinical regressions of solid tumors have been reported with certain types of cancer vaccines. While passive immunotherapies with antibody to tumor antigens (Avastin, Herceptin, Erbitux, Rituxan, Bexxar) are being used to treat selected types of cancers, active immunotherapies may be better suited to potentially elicit a sustained immune response, particularly when administered in an adjuvant setting. This review covers the potential and issues with specific active immunotherapies (SAI) for the treatment of cancer.
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PMID:Specific active immunotherapy of cancer: potential and perspectives. 1847 80

Monoclonal antibodies have emerged as a class of novel oncology therapeutics. The selectivity and specificity, the unique pharmacokinetics, and the ability to engage and activate the immune system differentiate these biologics from traditional small molecule anticancer drugs. In this review, we focus on 4 antibodies approved for clinical use in treating solid tumors, trastuzumab (Herceptin) for breast cancer, bevacizumab (Avastin) for colorectal cancer and non-small cell lung cancer, cetuximab (Erbitux) for colorectal cancer and head and neck cancer, and panitumumab (Vectibix) for colorectal cancer. The anticancer effects of these antibodies derive from blockade of growth factor/receptor interaction and/or down-regulation of oncogenic proteins (eg, growth factor receptors) on the tumor cell surface, and for some of these antibodies from the ability to elicit effector mechanisms of the immune system, such as antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. The mechanism behind each antibody, the registration trials for their approved indications, and emerging indications are the focus of this article. We also review clinical considerations including commonly observed and antibody-related side effects, and dosing schedules. In addition, perspectives on challenges and opportunities of oncology antibody clinical development, antibody engineering, and the use of pharmacogenomics are presented.
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PMID:Antibody-based therapy for solid tumors. 1853 57

The E-cadherin transcriptional repressor Snail is a prognostic marker for metastatic breast carcinoma, as well as a critical determinant of tumor growth and recurrence. We define a non-angiogenic, autocrine function for the vascular endothelial growth factor-A (VEGF-A) in regulating Snail expression in breast tumor cells. The transfection of well-differentiated breast tumor cells with VEGF-A increases Snail mRNA and protein levels, resulting in reduced E-cadherin expression. Conversely, reducing endogenous VEGF-A expression in poorly differentiated breast tumor cells by siRNA transfection decreases Snail levels. Our studies demonstrate that VEGF and the VEGF receptor Neuropilin-1 increase Snail expression by suppressing the Glycogen Synthase Kinase-3 (GSK-3), an established inhibitor of Snail transcription and protein stability. The VEGF-A neutralizing antibody Avastin was recently approved by the FDA for the treatment of metastatic breast cancer. We present the provocative finding that beyond its anti-angiogenic activity, Avastin can reduce Snail expression in breast tumor cells. Collectively, this work describes a novel autocrine function for VEGF in breast tumor cells in driving the expression of Snail, a breast tumor progression factor. Based on our demonstration that Avastin reduces Snail expression in breast tumor cells, we propose that the treatment of early stage breast cancer patients with Avastin may impede tumor progression.
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PMID:Vascular endothelial growth factor-A stimulates Snail expression in breast tumor cells: implications for tumor progression. 1855 84

Metastatic renal cell carcinoma (RCC) associates with overproduction of vascular endothelial growth factor (VEGF) due to the mutation/inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Herein we demonstrate that implantation of human RCC tumor cells into athymic nude mice promotes the appearance of VEGF receptor 1 (VEGFR1)/CD11b double-positive myeloid cells in peripheral blood. Avastin-mediated VEGF neutralization was capable of significantly reducing the numbers of circulating VEGFR1+ myeloid cells. Conversely, up-regulation of VEGFR1 by myeloid cells could also be achieved in vitro by coculturing bone marrow cells with RCC-conditioned medium or by short-term exposure of naive myeloid cells to oxidative stress. Treatment of myeloid cells with H2O2, lipid peroxidation product 4-hydroxy-2(E)-nonenal, or an inhibitor of thioredoxin reductase all resulted in increased expression of VEGFR1. Furthermore, after exposure to oxidative stress, myeloid cells acquire immunosuppressive features and become capable of inhibiting T cell proliferation. Data suggest that tumor-induced oxidative stress may promote both VEGFR1 up-regulation and immunosuppressive function in bone marrow-derived myeloid cells. Analysis of tumor tissue and peripheral blood from patients with metastatic RCC revealed that VEGFR1+ cells can be also found in cancer patients. Restoration of immunocompetence in metastatic RCC patients by pharmacological elimination of VEGFR1+ cells may have a significant impact on the therapeutic efficacy of cancer vaccines or other immune-based therapies.
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PMID:Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. 1856


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