Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006826 (cancer)
 1,092,456 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal cell carcinoma accounts for approximately 3% of adult malignancies and 90%-95% of neoplasms arising from the kidney. It is characterized by a lack of early warning signs, diverse clinical manifestations, resistance to radiation and chemotherapy, and infrequent but reproducible responses to immunotherapy with agents such as interferon alpha (IFNa) and interleukin 2 (IL-2). International studies have shown objective response rates of < 15% in patients with advanced and metastatic disease, with 5-year disease-specific survival ranging between 0-20%. Considering these poor outcomes, renal cancers' very vascular nature and overexpression of receptors for vascular endothelial growth factor (VEGF), various biologic and angio-suppressive therapies are being evaluated in clinical trials. Promising results in terms of overall response rate and median time to progression have been reported especially as second-line therapy following cytokine failure, a setting where no effective systemic therapy has been recognized (SU011248, Bay 43-9006, Bevacizumab and Erlotinib). While confirmatory studies are ongoing, other novel treatments in first line trials (CCI-779, Infliximab, PTK-787, and Thalidomide) have drawn international attention. This review, analyzing basic translational research principles, will summarize the available data on the use of these new therapeutic approaches in RCC.
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PMID:New treatments for metastatic kidney cancer. 1578 Jan 70

Vascular endothelial growth factor (VEGF) plays a crucial role in the growth and metastatic spread of cancer. Bevacizumab (Avastin) is the first commercially available VEGF inhibitor, earning U.S. Food and Drug Administration (FDA) approval in February 2004. In combination with fluorouracil (5-FU)-based chemotherapy, this agent significantly prolongs overall and progression-free survival of patients with metastatic colorectal cancer. This review details the emerging role of the drug, its unique side effects, and other practical considerations related to bevacizumab therapy. Ongoing trials attempting to define additional indications for bevacizumab as well as the development of other promising angiogenesis inhibitors are also reviewed.
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PMID:The horizon of antiangiogenic therapy for colorectal cancer. 1582 49

Angiogenesis is a strongly regulated process, which is dependent upon a complex interplay between inhibitory and stimulatory angiogenic factors. It is essential for tumor growth and metastasis: increased angiogenesis is correlated with poor prognosis in cancer patients. Many novel compounds that potently inhibit formation of neoplastic blood vessels have been recently developed. Major categories of angiogenesis antagonists include protease inhibitors, direct inhibitors of endothelial cell proliferation and migration, angiogenic growth factor suppressors, inhibitors of endothelial-specific integrin/survival signalling, copper chelators, and inhibitors with other specific mechanisms. There is increasing interest in developing angio-suppressive agents for colorectal cancer treatment. Some 20 direct and indirect antiangiogenesis drugs are currently being evaluated in clinical trials in colorectal cancer (CRC). Promising results have been reported. These include an increase in overall survival and reduction in the risk of death (Bevacizumab), reversal of cellular resistance (Cetuximab) and activity as second-line therapy in patients who have exhausted other available treatment options (Cetuximab, ABX-EGF, PTK-787, Gefitinib, Erlotinib). This review will outline the mechanisms of action of the principal antiangiogenic drugs, summarize the available data on the use of these new drugs in colorectal cancer, discuss their impact in clinical practice and offer a glimpse into how antiangiogenetic therapy will be integrated into the future care of patients with gastrointestinal cancers.
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PMID:Colorectal cancer and antiangiogenic therapy: what can be expected in clinical practice? 1589 May 25

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
Curr Cancer Drug Targets 2005 May
PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18

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

Angiogenesis is crucial to tumour initiation, survival and metastasis. Vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors in cancer development. Bevacizumab (a humanised monoclonal antibody against VEGF) has a reasonable safety profile and proven efficacy in a phase III trial in advanced colorectal cancer. Efficacy of Bevacizumab also looks promising in non small cell lung cancer, renal cancer and a variety of other solid tumours. Questions still surround optimal dosing and the appropriate selection of patients who are most likely to benefit. Future trials will address these questions and provide further translational insights.
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PMID:Bevacizumab--current status and future directions. 1677 23

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

Bevacizumab is a humanised monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), the key mediator of tumour angiogenesis, and has been shown to improve survival when given with chemotherapy to patients with metastatic colorectal cancer. In a pivotal Phase III clinical trial, 813 subjects were treated with irinotecan, 5-fluorouracil (5-FU) and leucovorin and randomised to receive placebo or bevacizumab. Median survival for the group receiving bevacizumab was increased by 30%, from 15.6 to 20.3 months (p < or = 001). Other Phase II and III studies in colorectal cancer have demonstrated a benefit when bevacizumab is added to regimens of 5-FU and leucovorin, and 5-FU, leucovorin and oxaliplatin. The toxicity associated with bevacizumab is generally mild, consisting of manageable hypertension, clinically insignificant proteinuria and mild mucosal bleeding. Infrequent severe toxicities have been reported, consisting of arterial thrombosis and gastrointestinal perforations (1.5%). Bevacizumab represents the first angiogenesis modulator that has a proven benefit in cancer therapy.
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PMID:Bevacizumab in the treatment of colorectal cancer. 1601 43

From having been a 'single-drug not very interesting cancer type' from a medical treatment perspective, treatment of colorectal cancer (CRC) has during the past five years become a more complex issue of the appropriate use of several cytotoxic drugs sometimes integrated with advanced metastatic surgery with curative intent. The new drugs have provided significant benefit to the patients, so far mostly in the metastatic setting but also in adjuvant treatment. The significant progress in molecular and tumour biology has produced a great number of new 'targeted' drugs that are now in various stages of clinical development. Two of these drugs, the monoclonal antibodies bevacizumab (Avastin) and cetuximab (Erbitux), directed against VEGF and EGFR, respectively, have recently been approved within the EU for use in metastatic CRC. This Nordic Expert Consensus Report summarizes the current status of chemotherapy in metastatic CRC, overviews the clinical status of targeted drugs in CRC and, finally, provides guidelines for the routine clinical use of bevacizumab and cetuximab based on the most recently available clinical data.
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PMID:Targeted drugs in metastatic colorectal cancer with special emphasis on guidelines for the use of bevacizumab and cetuximab: an Acta Oncologica expert report. 1607 90


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