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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The field of cancer research has seen a marked shift in the past decade towards the exploration and development of non-conventional antitumour agents. One of the most widely studied approaches to therapy during this period has been that of antiangiogenesis. The published clinical trials and subsequent FDA approval (in February 2004) of the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin, Genentech) for the treatment of colorectal cancer marked a milestone for antiangiogenesis therapy. Currently, preclinical and clinical research involving therapeutic targeting of VEGF and other mediators of angiogenesis continues in multiple tumour types. In addition to colorectal cancer, angiogenesis inhibitors are being investigated in the treatment of renal cell carcinoma, head and neck carcinoma, lung cancer, breast cancer, prostate cancer, and a variety of haematological malignancies. This article will discuss the background of antiangiogenesis research, preclinical and clinical data relating to the use of bevacizumab in the treatment of colorectal cancer, other completed clinical trials involving antiangiogenesis agents, and the potential future utility of these agents in the treatment of malignancy.
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PMID:Angiogenesis inhibitors in the treatment of cancer. 1608 56

Angiogenesis, the process of generating new capillary blood vessels, is a fundamental requirement for normal physiological processes including embryogenesis, reproductive function and wound healing. Angiogenesis is also implicated in various pathological conditions including age-related retinal macular degeneration, diabetic retinopathy, rheumatoid arthritis, psoriasis and cancer growth and metastasis. Vascular endothelial growth factor (VEGF) is one of the best characterized of the pro-angiogenic growth factors, and multiple strategies have been developed to inhibit this pathway. Bevacizumab, a monoclonal antibody developed against VEGF, has shown initial preclinical and clinical activity. This review discusses the critical role of VEGF and summarizes the available data on the use of bevacizumab in colorectal cancer.
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PMID:Clinical experience with bevacizumab in colorectal cancer. 1610 Nov 90

The treatment of cancer by targeting angiogenesis and depriving growing tumors of their blood supply has been recognized as an interesting therapeutic possibility for several decades. A multitude of development programs investigating both low-molecular-weight substances and biologicals, in particular monoclonal antibodies (mAbs), have been instigated. The generation of human or human-like mAbs has led to the recent development of therapeutic antibodies that are potentially highly beneficial in the treatment of cancer. Avastin, which binds to the pro-angiogenic factor vascular endothelial growth factor, is one of the most promising of these antibodies, and has proved beneficial in the treatment of colorectal, lung and breast cancer, with a potential to be used also in other types of cancer. However, as angiogenesis is a complex process controlled by both pro-angiogenic as well as anti-angiogenic factors, several research and development programs targeting different pro-angiogenic factors, receptors and antigens that are selectively expressed on cells in newly formed blood vessels are under way. At BioInvent International AB, research is focused on angiomotin, a newly discovered receptor for the anti-angiogenic factor angiostatin, and on the pro-angiogenic factor placenta growth factor.
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PMID:Targeting angiogenesis with antibodies for the treatment of cancer. 1611 94

The formation of a 'tumor-associated vasculature', a process referred to as tumor angiogenesis, is a stromal reaction essential for tumor progression. Inhibition of tumor angiogenesis suppresses tumor growth in many experimental models, thereby indicating that tumor-associated vasculature may be a relevant target to inhibit tumor progression. Among the antiangiogenic molecules reported to date many are peptides and proteins. They include cytokines, chemokines, antibodies to vascular growth factors and growth factor receptors, soluble receptors, fragments derived from extracellular matrix proteins and small synthetic peptides. The polypeptide tumor necrosis factor (TNF, Beromun) was the first drug registered for the regional treatment of human cancer, whose mechanisms of action involved selective disruption of the tumor vasculature. More recently, bevacizumab (Avastin), an antibody against vascular endothelial growth factor (VEGF)-A, was approved as the first systemic antiangiogenic drug that had a significant impact on the survival of patients with advanced colorectal cancer, in combination with chemotherapy. Several additional peptides and antibodies with antiangiogenic activity are currently tested in clinical trials for their therapeutic efficacy. Thus, peptides, polypeptides and antibodies are emerging as leading molecules among the plethora of compounds with antiangiogenic activity. In this article, we will review some of these molecules and discuss their mechanism of action and their potential therapeutic use as anticancer agents in humans.
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PMID:Antiangiogenic peptides and proteins: from experimental tools to clinical drugs. 1626 19

For several decades, 5-fluorouracil (5-FU) with or without leucovorin defined the standard of care for the treatment of metastatic colorectal cancer (CRC). The addition of other chemotherapy regimens to 5-FU has improved survival, but often at the expense of increased toxicity. Recent advances in our understanding of the molecular basis of CRC have led to the production of novel targeted agents, such as bevacizumab (Avastin). Bevacizumab is currently approved for the first-line treatment of metastatic CRC and is currently being tested in combination with standard therapies for a range of indications. Phase II/III trials have demonstrated that the addition of bevacizumab to 5-FU-based first-line chemotherapy improves survival, progression-free survival and response rate compared with chemotherapy alone. Combination therapy does not appear to exacerbate side effects known to be associated with the chemotherapy regimen. The most common side effects attributable to bevacizumab therapy include hypertension, proteinuria and bleeding. Although uncommon, gastrointestinal perforation and arterial thromobembolic events are the most serious side effects reported to date. Bevacizumab is currently being evaluated in combination with oxaliplatin (Eloxatin)-based therapies and preliminary data are encouraging. Ongoing trials of bevacizumab in combination with standard first-line chemotherapy regimens will evaluate bevacizumab's potential in a range of cancer types. .
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PMID:Bevacizumab combined with standard fluoropyrimidine-based chemotherapy regimens to treat colorectal cancer. 1630 32

Bevacizumab (Avastin), the first approved therapy designed to inhibit tumor angiogenesis, has significant clinical benefits in the management of colorectal cancer (CRC). When bevacizumab is added to IFL (5-fluorouracil [5-FU]/leucovorin [LV]/irinotecan [Camptosar)]) as first-line therapy for metastatic CRC, significant overall and progression-free survival benefits are obtained. Similar survival benefits may be achieved when bevacizumab is added to 5-FU/LV alone. In addition, additive and synergistic effects with a range of chemotherapeutic agents illustrate that bevacizumab has considerable potential in combination with existing therapeutic options. Clinical data indicate that bevacizumab is the only agent in addition to chemotherapy that has demonstrated survival benefit in the first- and second-line settings. In addition, bevacizumab is expected to produce clinical benefit in the adjuvant setting: inhibition of vascular endothelial growth factor should prevent the angiogenic switch in micrometastases, which is a key factor in malignancy. The clinical program is examining the activity of bevacizumab in combination with the likely future standard of care in both the metastatic and adjuvant treatment settings. Phase III trials (NO16966C, CONcePT and TREE-2) are studying the benefit of combining bevacizumab with oxaliplatin (Eloxatin)-based regimens. Similarly, in the adjuvant setting, phase III trials are assessing the efficacy and tolerability of bevacizumab in combination with oxaliplatin-based chemotherapy (AVANT, NSABP C-08).
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PMID:The future development of bevacizumab in colorectal cancer. 1630 34

At first glance, the antiangiogenic drug Avastin (bevacizumab) must paradoxically normalize angiogenesis, in order to potentiate chemotherapy. However, this may be only a part of the story. Here I discuss that the synergy between Avastin and chemotherapy is also consistent with the classic notion that antiangiogenic therapy actually inhibits angiogenesis. It has been previously predicted that inhibition of angiogenesis (action) will induce a reactive resistance (reaction), which is mediated by the HIF-1/VEGF pathway in cancer cells, thus allowing both endothelial and cancer cells to resist therapy. Therefore, inhibitors of the reactive resistance are needed to potentiate anti-angiogenic therapy. In the combination of chemotherapy plus Avastin, it is chemotherapy that is the principal antiangiogenic agent. This role of chemotherapy requires that something should be added to block the reaction. And this is exactly what Avastin does (by blocking VEGF). While chemotherapy inhibits angiogenesis, Avastin abrogates the reactive resistance, sensitizing both endothelial and cancer cells to therapy.
Cancer Biol Ther 2005 Dec
PMID:How Avastin potentiates chemotherapeutic drugs: action and reaction in antiangiogenic therapy. 1632 83

Progression of cancer is dependent on acquisition of vascular networks within the tumor. Tumor angiogenesis is dependent on up-regulation of angiogenesis stimulators to overcome the endogenous anti-angiogenic barrier. Such disruption of angiogenesis balance to favor neovascularization is a key step for progression of tumor growth and metastasis. In this regard, the vascular basement membrane and the extracellular matrix have been found to be rich sources of angiogenesis stimulators and inhibitors that become bioavailable on proteolysis of the matrix by tumor microenvironment-related enzymes. In this review the subgroup of endogenous angiogenesis stimulators and inhibitors is discussed, and their mechanism of action during tumor angiogenesis is evaluated. The role in regulating tumor growth and the possibility of using them as prognostic markers for human gastrointestinal cancers is discussed. Furthermore, we specifically address the role of vascular endothelial growth factor in human gastrointestinal cancers and discuss the development and use of bevacizumab (Avastin; anti-vascular endothelial growth factor antibody [Genentech, CA]) in the treatment of colorectal and other gastrointestinal cancers.
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PMID:Endogenous stimulators and inhibitors of angiogenesis in gastrointestinal cancers: basic science to clinical application. 1634 73

In the quest to discover new research tools and to develop better agents in the fight against cancer, two antibodies, G6 and B20-4, were isolated from synthetic antibody phage libraries. Unlike the AVASTINtrade mark antibody, a recently approved agent for the treatment of patients with colorectal cancer, B20-4 and G6 bind and block both human and murine vascular endothelial growth factor (VEGF). Here we have analyzed and compared the binding epitopes on VEGF for these three antibodies using alanine-scanning mutagenesis and structural analyses. The epitopes recognized by both synthetic antibodies are conserved between human and mouse VEGF, and they match closely to the receptor epitopes both structurally and functionally. In contrast, the Avastin epitope overlaps minimally with the receptor binding surface and centers around a residue that is not conserved in mouse. Our structural and functional analyses elucidate the cross-species reactivity of all three antibodies and emphasize the potential advantages of antibody generation using phage display as the resulting antibodies do not depend on sequence differences across species and preferentially target natural protein-protein interaction surfaces.
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PMID:Structure-function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab. 1637 45

The scientific rationale to block angiogenesis as a treatment strategy for human cancer has been developed over the last 30 years, but is only now entering the clinical arena. Preclinical studies have demonstrated the importance of the vascular endothelial growth factor (VEGF) pathways in both physiologic and pathologic angiogenesis, and have led to the development of approaches to block its role in tumor angiogenesis. Bevacizumab is an antibody to VEGF and has been shown to prolong survival when given with chemotherapy in the treatment of metastatic colorectal cancer (CRC). Although this is the first anti-angiogenic treatment to be approved for the treatment of human epithelial malignancy, a number of other approaches currently are in development. Soluble chimeric receptors to sequester serum VEGF and monoclonal antibodies against VEGF receptors have both shown considerable promise in the laboratory and are being brought into clinical investigation. A number of small-molecule tyrosine kinase inhibitors that have activity against VEGF receptors also are in clinical trials. Although these novel treatments are being pioneered in CRC, anti-angiogenic approaches also are being tested in the treatment of other gastrointestinal malignancies. Anti-VEGF therapy has shown promise in such traditionally resistant tumors as pancreatic cancer and hepatocellular carcinoma. This review will examine the preclinical foundation and then focus on the clinical studies of anti-VEGF therapy in gastrointestinal cancers.
Cancer Invest 2005
PMID:Anti-angiogenic treatment of gastrointestinal malignancies. 1637 90


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