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)

Angiogenesis, the formation of blood vessels, is a vital process in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a potential target for antiangiogenic therapy because its overexpression has been associated with tumor vascularity, poor prognosis, and aggressive disease in many malignancies, including colorectal cancer (CRC). Bevacizumab is a recombinant humanized monoclonal antibody against VEGF. It is the first angiogenesis inhibitor to show significant activity in patients and, when combined with chemotherapy, leads to a significant survival benefit in CRC. This monoclonal antibody has been approved for first-line therapy in combination with intravenous 5-fluorouracil-containing regimens in patients with metastatic CRC. Vatalanib (PTK787/ZK222584) is an oral antiangiogenic tyrosine kinase inhibitor of the VEGF receptor. Currently, it is being evaluated in combination with FOLFOX (5-fluorouracil/leucovorin/oxaliplatin) in metastatic CRC. This article reviews the process of angiogenesis and the successful translation of antiangiogenic agents into the clinic. Specifically, studies evaluating VEGF-targeted agents in combination with oxaliplatin-containing regimens in CRC are discussed.
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PMID:Combining anti-VEGF approaches with oxaliplatin in advanced colorectal cancer. 1547 83

Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy represents a new strategy for the development of anti-cancer therapies. In recent years, there has been made great progress in anti-angiogenic therapy. As far as the passive immunotherapy is concerned, a recombinant humanized antibody to vascular endothelial growth factor (VEGF)--Avastin has been approved by FDA as the first angiogenesis inhibitor to treat colorectal cancer. For active specific immunotherapy, various strategies for cancer vaccines, including whole endothelial cell vaccines, dendritic cell vaccines, DNA vaccines, and peptides or protein vaccines, have been developed to break immune tolerance against important molecules associated with tumor angiogenesis and induce angiogenesis-specific immune responses. This article reviews the angiogenesis-targeted immunotherapy of tumor from the above two aspects.
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PMID:Immunotherapy of tumor by targeting angiogenesis. 1562 Jan 11

Pathologic angiogenesis induced by a tumor is essential for its survival. The promise of tumor inhibition by targeting angiogenesis over the past several years has translated into numerous ongoing clinical trials. Recently, in a phase III trial involving patients with metastatic colorectal cancer, Bevacizumab (Genentech, Inc, San Francisco, CA), a recombinant humanized monoclonal antibody against vascular endothelial growth factor used in conjunction with standard chemotherapy was shown to increase survival, progression-free survival, response rate, and duration of response compared to chemotherapy alone. Thus far, duration of the increased response remains less than 6 months. The majority of deaths in patients with colorectal cancer are related to hepatic metastases. It is hoped that novel approaches directed at the complex interactions between tumor and microenvironment in the angiogenic process will strengthen the therapeutic armamentarium against hepatic malignancies.
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PMID:Hepatic tumor growth: target for angiogenesis inhibition? 1570 41

Many novel antiangiogenic agents are currently in various phases of clinical testing. These agents tend to be cytostatic, and therefore few responses are observed with conventional imaging by computerized tomography. Furthermore, toxicity with these agents is seen when the maximum-tolerated dose is combined with chemotherapy. Hence, there is a need to develop imaging strategies that can determine the minimum and optimum biologically active doses. There is increasing awareness of the need to obtain evidence of drug activity through the use of surrogate markers of the biologic mechanism of action during early clinical trials, in addition to determining the pharmacokinetics, toxicity profile, and maximum-tolerated dose. One of the major impediments to the rapid development of antiangiogenic agents in the past has been the lack of validated assays capable of measuring an antiangiogenic effect directly in patients. Recently, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has emerged as a useful technique for noninvasive imaging of tumor vasculature in preclinical and clinical models. The problem of tumor heterogeneity remains to be addressed. The major challenge is the standardization of the technique worldwide for the purpose of early clinical studies that are likely to be multicenter. Convincing data on correlations between changes observed through molecular imaging and changes in tumor angiogenesis, and hence tumor biology, are still lacking. Whether this would translate into a survival advantage remains to be seen. The ultimate test of the surrogate biological end points determined by molecular imaging will occur in randomized phase III trials. Results of the first randomized trial that showed a survival advantage in favor of antiangiogenic agents were released at the American Society of Clinical Oncology meeting in 2003. There it was reported that the combination of 5-fluorouracil, leucovorin, and irinotecan (Camptosar; Pfizer Pharmaceuticals; New York, NY) with anti-vascular endothelial growth factor antibody (bevacizumab-Avastin; Genentech, Inc.; South San Francisco, CA) was superior to the chemotherapy regimen alone when used to treat patients with metastatic colorectal cancer. However, until further phase III clinical trials confirm these results, surrogate end points of clinical efficacy of the newer agents are urgently needed so that development of ineffective drugs can be halted early. This review briefly discusses the role of molecular imaging in general, and DCE-MRI in particular, in relation to treatment with antiangiogenic agents and highlights some of the difficulties encountered in this area.
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PMID:Molecular imaging of antiangiogenic agents. 1570 11

Despite advances in understanding and treatment, ovarian cancer remains a major cause of cancer mortality worldwide. Debulking surgery and paclitaxel/carboplatin chemotherapy induce good initial responses in most patients, although most cases of advanced disease are not controlled. Monoclonal antibodies hold promise as a potential incremental advance for the treatment of the disease. Antibodies can be used to stimulate the immune response, target tumor-specific receptors to induce antibody-dependent cellular cytotoxicity or interfere with biologic pathways. They can also be used to deliver therapeutic radioisotopes to malignant cells. Oregovomab is in Phase III clinical trials as a consolidation treatment post front-line therapy to trigger tumor-specific cellular immunity. Bevacizumab, which blocks vascular endothelial growth factor, will be entering Phase III as an adjuvant to front-line chemotherapy with a direct effect on angiogenesis. Additional immunostimulating, immune counter-regulatory and receptor-targeting approaches are also reviewed. The family of epidermal growth factor receptors including epidermal growth factor receptor 1 (HER-1) and 2 (HER-2) are both expressed in ovarian cancer and are the subject of ongoing research and development. The recent disappointing results with 90-yttrium-labeled anti-HMFG by single intraperitoneal administration have left the radiopharmaceutical field without a Phase III candidate. Identification of novel targets may advance this therapeutic area in the future. The rapid advances in the fields of immunoregulation and tumor biology should permit an accelerated introduction of antibodies for the treatment of ovarian cancer. These antibodies could complement novel small molecules that are also in development.
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PMID:Monoclonal antibody therapy of ovarian cancer. 1575 41

Fluorouracil (FU) has been the mainstay of treatment for metastatic colorectal cancer (mCRC) for many years. However, in recent years, newer chemotherapeutic agents, particularly irinotecan (Campostar; Pfizer Pharmaceuticals, New York, NY, http://www.pfizer.com) and more recently oxaliplatin (Eloxatin; Sanofi-Aventis Inc., New York, NY, http://www.sanofi-aventis.com), have been shown to improve survival in combination with FU-based therapies. These agents were therefore incorporated into first- and second-line treatment strategies. The development of targeted agents that are tumor specific with better toxicity profiles than chemotherapeutic agents has widened the spectrum of therapies for this disease. The U.S. Food and Drug Administration (FDA) recently approved two targeted agents for treating mCRC: an antivascular endothelial growth factor monoclonal antibody (mAb), bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com), in combination with first-line 5-FU-based chemotherapy regimens and the human epidermal growth factor receptor (HER-1/EGFR)-targeted mAb cetuximab (Erbitux; ImClone Systems, Inc., New York, NY, http://www.imclone.com) as monotherapy or in combination with irinotecan as second-line therapy in refractory cancer. These newer, more effective agents are improving clinical outcome for patients with mCRC. However, as the number of agents has increased, choosing the most effective treatment strategy has become increasingly complex. This review discusses the role of the individual agents in the treatment of mCRC and identifies the most effective regimens.
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PMID:Critical evaluation of current treatments in metastatic colorectal cancer. 1582 Dec 45

Bevacizumab (Avastin, Genentech) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), a critical angiogenic factor involved in both physiological and pathological conditions. It has been recently approved by the US FDA as a first-line therapy for widespread metastatic colorectal cancer. This report is a detailed biological characterization of bevacizumab in a variety of in vitro models. It is shown that bevacizumab potently neutralizes VEGF and blocks its signal transduction through both the VEGFR-1 and VEGFR-2 receptors, as demonstrated by the inhibition of VEGF-induced cell proliferation, survival, permeability, nitric oxide production, as well as migration and tissue factor production. Although bevacizumab retains the ability to bind to human Fcgamma receptors and complement protein C1q, it does not demonstrate cell or complement-mediated cytotoxicity in either VEGF producing or targeting cells. Thus the mechanism of anti-tumor activity of bevacizumab is most likely due to its anti-angiogenesis effect through binding and neutralization of secreted VEGF.
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PMID:Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. 1588 77

The improved survival associated with adding the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to chemotherapy for the treatment of patients with metastatic colorectal cancer demonstrates the importance of targeting collateral cells involved in tumor growth, progression, and metastatic spread. Based on the Gompertzian model of tumor growth, adding anti-VEGF agents to standard chemotherapy may be especially effective in early stages of cancer. By improving chemotherapy delivery to the tumor and inhibiting regrowth between treatment cycles, anti-VEGF agents may alter the growth pattern of a tumor such that it is more susceptible to eradication. These concepts also suggest that anti-VEGF agents could enhance the effectiveness of chemotherapy given conventionally or in a dose-dense fashion. As such, it is possible that the effectiveness of chemotherapy could be maintained or improved, even at lower cumulative doses, which may improve its tolerability. Additionally, the effects of anti-VEGF agents on metronomic chemotherapy, which is reported to have antiangiogenic properties on its own, warrant further evaluation. Preclinical data demonstrate that cytostatic angiogenesis inhibitors are potent complementary agents to metronomic chemotherapy, producing sustained complete regressions in some models of human cancer. Dose-dense and metronomic chemotherapy have in common a shortened dosing interval and resultant increased and/or prolonged exposure of tumor cells to chemotherapy in vivo. Optimizing the use of anti-VEGF agents in the clinic demands further investigation of the most appropriate way to combine them with chemotherapy, particularly regimens designed to exploit known tumor growth patterns and those designed to target the endothelial cells involved in neovascularization with multiple agents.
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PMID:Clinical implications of antiangiogenic therapies. 1593

The hypothesis that tumor growth and metastasis is angiogenesis-dependent was proposed by Judah Folkman in 1971. Its major implication is that blocking angiogenesis could be a strategy for arresting tumor growth. This hypothesis is now supported by extensive experimental evidence, and hence the angiogenic switch and microvascular endothelial cells recruited by the tumor have emerged as important targets in cancer therapy. A large number of proangiogenic and antiangiogenic factors have been discovered. At least three angiogenesis inhibitors have received FDA approval in the US, with Avastin (anti-VEGF-antibody) also approved in 26 other countries. The recognition that antiangiogenic therapy is becoming the fourth therapeutic modality in addition to surgery, chemotherapy and radiotherapy underlines the urgent need to understand the systems biology of the antiangiogenic response. A particularly important question for cancer therapy is whether antiangiogenic therapy will also face the same drug resistance as one sees with other treatment modalities. Recently, the cellular signaling induced by the endogenous angiogenesis inhibitor - endostatin - was dissected revealing that the antiangiogenic response is characterized by a large number of individual genetic signals, which are highly coordinated and interdependent. The objective of this review is to elucidate the multifaceted nature of tumor angiogenesis, and to discuss the subtle but important distinctions that exist between variations in tumor responsiveness that evolve with antiangiogenic therapy and the classic resistance that frequently develops with conventional therapy. Furthermore, this review discusses the implications of current findings for cancer treatment and potential ways of overcoming or predicting tumor resistance to these agents.
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PMID:Endostatin: the logic of antiangiogenic therapy. 1593 43

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in vivo. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high affinity VEGF receptors. VEGF plays an essential role in developmental angiogenesis and is important also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.
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PMID:Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. 1595 88


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