Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solid tumors consist of several components, including normal and stromal cells, extracellular matrix, and vasculature. To grow and metastasize, tumors must stimulate the development of new vasculature through a process known as angiogenesis. Unlike normal blood vessels, tumor blood vessels are chaotic, irregular, and leaky, which leads to uneven delivery of nutrients and therapeutic agents to the tumor. Conventional therapies target neoplastic cells within a tumor; however, tumor vasculature is emerging as an important target for anticancer therapy. Antiangiogenic therapy offers several potential advantages as an approach to cancer treatment, notably physical accessibility and genetic stability of target cells. Vascular endothelial growth factor (VEGF), a central mediator of angiogenesis, has emerged as an important target for antiangiogenic therapy. In preclinical studies, treatment of human tumor xenografts in immunodeficient mice with the anti-VEGF monoclonal antibody A4.6.1 led to reduced tumor vessel permeability and caused vascular regression. The reduced vascular permeability, resulting from inhibition of VEGF, led to increased delivery of oxygen and therapeutic agents to tumors. Anti-VEGF therapy was effectively combined with other treatment modalities, including radiation, antihormonal, antibody, and chemotherapies in multiple preclinical models. Currently, several phase 3 clinical trials in various cancer types are under way to establish the efficacy of antiangiogenic therapy with a recombinant humanized anti-VEGF monoclonal antibody, bevacizumab (Avastin, rhuMAb-VEGF; Genentech, South San Francisco, CA), in combination with chemotherapeutic agents.
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PMID:Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. 1251 32

The limited effectiveness of chemotherapy in esophageal cancer used to palliate metastatic disease or to combine with radiotherapy in locally advanced disease has prompted the evaluation of new systemic agents. Irinotecan (CPT-11, Camptosar) has shown promising activity in a number of gastrointestinal cancers, including esophageal cancer. The phase II evaluation of the combination of weekly irinotecan and cisplatin has shown encouraging response rates exceeding 30% to 50% in esophageal and gastric cancer. Novel regimens include the combination of irinotecan with mitomycin (Mutamycin), the taxanes docetaxel (Taxotere) and paclitaxel, and continuous infusion fluorouracil (5-FU). Irinotecan is an active radiosensitizer, and trials have evaluated the combination of irinotecan with concurrent radiotherapy. We completed a phase I trial combining weekly irinotecan, cisplatin, and concurrent radiotherapy in locally advanced esophageal cancer. Minimal toxicity has been observed, with no grade 3/4 esophagitis or diarrhea, and hematologic toxicity was also surprisingly minimal. Full doses of weekly irinotecan (65 mg/m2) and cisplatin (30 mg/m2) could be combined safely with concurrent radiotherapy, with a significant rate of pathologic complete response. Phase II evaluation of this chemoradiotherapy regimen as preoperative therapy is planned at single institutions and at the cooperative group level in the United States. Further phase I and II investigation of combined irinotecan, cisplatin, and concurrent radiation is ongoing with the addition of targeted agents, including celecoxib (Celebrex), cetuximab (Erbitux), and bevacizumab (Avastin). Alternative combinations of irinotecan with radiotherapy, including the addition of docetaxel and continuous infusion 5-FU, are also undergoing phase I and II evaluation.
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PMID:Irinotecan in esophageal cancer. 1456 46

In colorectal cancer, increased expression of the angiogenesis promoter vascular endothelial growth factor correlates with invasiveness, vascular density, metastases, recurrence and prognosis. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor. In recent clinical trials, bevacizumab has been shown to prolong the time to disease progression and the survival of patients with colorectal cancer. In six patients with adenocarcinoma of the rectum, bevacizumab decreased tumour blood perfusion and volume, interstitial fluid pressure, the number of circulating endothelial cells and fluorodeoxyglucose uptake. Surgical specimens showed a marked response in all six patients with only microscopic disease in five of the patients. These effects of bevacizumab on the vascular biology of tumours probably underlie the progression and survival benefits observed in clinical trials of colorectal cancer.
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PMID:Vascular biology support for the use of bevacizumab in colorectal cancer. 1517 56

Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors. Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.
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PMID:Bevacizumab in the treatment of breast cancer: rationale and current data. 1517 15

Colorectal cancer remains one of the major causes of cancer death worldwide, but the past few years have witnessed the development of a number of new, effective treatment options, which have led to considerable improvement in the survival rate for patients suffering from this common cancer. The advent of agents such as capecitabine (Xeloda), irinotecan (Camptosar), and oxaliplatin (Eloxatin), and newer molecular targeted agents such as cetuximab (Erbitux) and bevacizumab (Avastin) brought innovation to the treatment of colorectal cancer. Oncologists are no longer restricted to using fluorouracil and its variations as the only active treatment, and the number of patients who are able to live longer continues to increase. Patients presenting with stage III cancer can expect a greater chance for cure, and those presenting with metastatic disease can expect a median survival approaching 2 years.
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PMID:Progress in the development of novel treatments for colorectal cancer. 1521 91

Drug treatment of colorectal cancer has made impressive progress during the past 10 years. In addition to fluorouracil new anticancer drugs like irinotecan and oxaliplatin have become available. The activity of fluorouracil was optimized by using schedules of prolonged infusion. Capecitabine is an oral pro-drug of fluorouracil. When colorectal metastases are limited to the liver they should be resected if possible. Sometimes they can be reduced in size by primary chemotherapy (downstaging) and resected later. Very new and exciting are reports with the monoclonal antibody bevacizumab in combination with chemotherapy. Bevacizumab blocks angiogenesis. So far it is available only in the USA.
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PMID:[New drugs for colorectal cancer]. 1548 60

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

Angiogenesis, the process of new blood vessel formation, is an essential step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a key mediator in this process, and elevated levels of this cytokine are observed in solid tumors and are correlated with worse clinical outcomes. Research has therefore focused on developing agents that target angiogenic factors such as VEGF in order to inhibit tumor growth. One such agent is bevacizumab, a humanized monoclonal antibody generated by engineering the VEGF-binding residues of a murine neutralizing antibody into the framework of a normal human immunoglobulin G. Bevacizumab recognizes VEGF receptors 1 and 2 and thus can neutralize the biologically active forms of VEGF that interact with these receptors. In addition, bevacizumab has shown antiangiogenic and antitumor activity in several cancer types, recently gaining approval from the FDA for use in combination with fluorouracil-based chemotherapy as a first-line treatment for metastatic cancer of the colon or rectum.
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PMID:Bevacizumab: antiangiogenic cancer therapy. 1575 67

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

Significant advances have been made in the treatment of advanced colorectal cancer over the past 5 years, namely due to the introduction of three novel cytotoxic agents-capecitabine (Xeloda), irinotecan (Camptosar), and oxaliplatin (Eloxatin)-and the recent approval of two biologic agents-bevacizumab (Avastin) and cetuximab (Erbitux). During this time period, the median survival of patients with advanced, metastatic disease has gone from 10 to 12 months to nearly 24 months. Intense efforts have focused on identifying novel targeted therapies that target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. Recent clinical trial results suggest that the anti-VEGF antibody bevacizumab can be safely and effectively used in combination with each of the active anticancer agents used in colorectal cancer. Despite the development of active combination regimens, significant improvements in the actual cure rate have not yet been achieved. Combination regimens with activity in advanced disease are being evaluated in the adjuvant and neoadjuvant settings. The goal is to integrate these targeted strategies into standard chemotherapy regimens so as to advance the therapeutic options for the treatment of advanced colorectal cancer. Finally, intense efforts are attempting to identify the critical molecular biomarkers that can be used to predict for either clinical response to chemotherapy and/or targeted therapies and/or the drug-specific side effects. The goal of such studies is to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with colorectal cancer.
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PMID:Current therapies for advanced colorectal cancer. 1594 40


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