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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of solid tumors depends upon an adequate supply of blood. This can be achieved by way of co-option of preexisting blood vessels and by the induction of angiogenesis. During the past 30 years, tumor angiogenesis had been found to play a crucial role in the progression of solid tumors. Tumor angiogenesis was found to be induced by a variety of pro-angiogenic cytokines of which the best characterized is vascular endothelial growth factor (VEGF). Indeed, the first FDA approved anti-angiogenic drug for the treatment of cancer is Avastin, a neutralizing antibody directed against VEGF. This review focuses on cytokines which have been reported to induce tumor angiogenesis.
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PMID:Pro-angiogenic cytokines and their role in tumor angiogenesis. 1700 65

The stroma of carcinomas shares several characteristics with inflamed tissues including a distorted vasculature, active angiogenesis and macrophage infiltration. In addition, the tumor interstitial fluid pressure (P(IF)) of the stroma is pathologically elevated. We show here that bevacizumab [rhuMab vascular endothelial growth factor (VEGF), Avastin], a monoclonal antibody to VEGF, at a dose of 5 mg/kg modulated inflammation in KAT-4 xenograft human anaplastic thyroid carcinoma tissue. At this dose, bevacizumab reduced the density of macrophages, MHC class II antigen expression by macrophages and IL-1beta mRNA expression. Furthermore, bevacizumab lowered tumor extracellular fluid volume, plasma protein leakage from tumor vessels, the number of CD31-positive structures and tumor P(IF). The tumor plasma volume and the number of alpha-smooth muscle actin-positive vessels, however, remained unchanged. Our data suggest that carcinoma cell-derived VEGF either directly or indirectly participates in maintaining an inflammatory microenvironment in experimental KAT-4 carcinoma. Furthermore, our data indicate that the reduction of inflammation resulting in reduced vascular permeability and decrease in the tumor extracellular fluid volume by bevacizumab contributes to reduced tumor P(IF).
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PMID:Inhibition of carcinoma cell-derived VEGF reduces inflammatory characteristics in xenograft carcinoma. 1701 8

Antiangiogenic therapy has emerged as an important concept in the treatment of solid tumors, including non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF) represents an important therapeutic target, as it is the primary mediator of angiogenesis and is induced by multiple tumor-relevant stimuli. The anti-VEGF monoclonal antibody bevacizumab has demonstrated a significant clinical benefit in patients with non-squamous cell NSCLC in a randomized phase III trial. The addition of bevacizumab to chemotherapy with paclitaxel plus carboplatin provided a significant survival benefit over chemotherapy alone. Bevacizumab is associated with an increased risk of severe bleeding; thus, patients should be carefully selected for bevacizumab treatment. Hypertension is also seen with bevacizumab but can be managed with antihypertensive agents. Ongoing studies are evaluating bevacizumab in other NSCLC settings and are attempting to identify predictive factors for responses to bevacizumab. Antiangiogenic approaches other than bevacizumab are also being investigated, including several small-molecule tyrosine kinase inhibitors that have demonstrated activity in small studies. In some cases, combination therapy with different targeted agents may provide the most comprehensive treatment approach. In a randomized phase II study, bevacizumab in combination with the epidermal growth factor receptor inhibitor erlotinib demonstrated efficacy similar to chemotherapy plus bevacizumab. Ongoing studies are continuing to investigate new agents and identify the patients most likely to benefit from antiangiogenic therapy.
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PMID:Angiogenesis inhibition in the treatment of lung cancer. 1714 57

Bevacizumab, the first approved vascular endothelial growth factor (VEGF)-targeted agent for metastatic colorectal cancer, continues to be developed in phase III trials in other tumor types. Its use is being explored not only in advanced disease, but also in earlier-stage disease in the adjuvant setting. Preclinical and clinical research is also addressing several potential strategies for maximizing the benefits of bevacizumab and other VEGF-targeted agents, including (1) dual inhibition of VEGF and platelet-derived growth factor signaling to target both the endothelial and the pericyte components of tumor vasculature; (2) combining VEGF-targeted agents with other targeted agents, such as inhibitors of HER2 or epidermal growth factor receptor signaling, which affect several angiogenic pathways; and (3) combining VEGF-targeted agents with low-dose, metronomic chemotherapy. The optimal dose and schedule of VEGF-targeted agents is another unanswered question. Further investigation of the mechanism of action and vascular effects of VEGF-targeted agents in humans will help to address these questions. Mechanistic studies in humans will be aided by the development and validation of surrogate clinical end points such as noninvasive assessment of hemodynamics and vascular changes within tumors, using imaging studies.
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PMID:Future directions in vascular endothelial growth factor-targeted therapy for metastatic colorectal cancer. 1714 24

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, was approved in 2004 for use in combination with intravenous 5-fluorouracil-based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab is the first approved agent that targets tumor angiogenesis. The pivotal phase III trial showed significantly greater overall and progression-free survival with the addition of bevacizumab to irinotecan, 5-fluorouracil, and leucovorin. These outcomes were observed irrespective of patients' pretreatment characteristics (age >/=65 years, >/=1 site of metastasis, or location of primary tumor). Furthermore, there was a significant survival benefit regardless of pretreatment biomarkers, including plasma vascular endothelial growth factor level, tumor thrombospondin and p53 expression, and mutational status in k-ras, b-raf, and p53. Analysis of data in responders and nonresponders showed a response-independent survival benefit, indicating that even those in whom there was not an objective tumor response by standard criteria benefited from the addition of bevacizumab. Preliminary data on the addition of bevacizumab to oxaliplatin- and capecitabine-based regimens for the first-line treatment of metastatic colorectal cancer show that these regimens are well tolerated, with consistent increases in objective response rates, time to progression, and overall survival. The survival advantages in patients with metastatic colorectal cancer with the addition of bevacizumab to chemotherapy support the use of this agent in first-line treatment.
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PMID:Bevacizumab in combination with chemotherapy: first-line treatment of patients with metastatic colorectal cancer. 1714 25

The current methods of treating cancer patients with chemotherapeutics do not account for interpatient variability in the expression of particular target genes. This variability leads to unpredictable tumor responses and host toxicity. The approach we have taken is to determine gene expression levels in the metabolic pathways of drugs used in the treatment of gastrointestinal tumors. One of the main obstacles in the evaluation and determination of these markers has been the limitations of available technology. Many advances have been made in the development of more sophisticated techniques and the ability to perform these techniques on paraffin-embedded tumor tissue. In fact, with the identification of genetic polymorphisms, these markers may be obtained from peripheral blood specimens, thus making access to tissues a moot issue. An immediate goal is the application of this nascent technology and incorporation of these data in prospective clinical trials that would stratify patients according to their molecular profile. The ability to predict with a high degree of accuracy which patients are likely to respond to treatment and identify those who are not likely to respond will significantly influence the design of new treatment regimens with fluoropyrimidines and platinum. Tumors with high TS, TP, and DPD expression levels should be treated with such non-TS-directed anticancer drugs as irinotecan or oxaliplatin, or in combination with 5-FU. Patients with high expression of ERCC1 should be treated with nonplatinum-based regimens, whereas patients with low levels would be good candidates for cisplatin or oxaliplatin. We now understand that molecular determinants play an important role in response to 5-FU. With the development of new effective anticancer drugs such as irinotecan and oxaliplatin, it is important to gain a better understanding about the metabolism of these new active agents and mechanisms of resistance. It is essential to understand why some patients develop life-threatening toxicity and why some tumors are resistant to irinotecan or oxaliplatin. With the integration of novel-targeted therapies such as Erbitux and Avastin, molecular characterization and profiling will become more important for patient selection. Preliminary data suggest that germ line polymorphisms of cyclin D and gene expression levels of VEGF are associated with efficacy of Erbitux therapy.
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PMID:Pharmacogenomics and colorectal cancer. 1716 68

Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has shown antitumor activity by inhibiting tumor angiogenesis in preclinical and clinical studies. However, bevacizumab monotherapy does not induce complete tumor regression. Therefore, additional treatments must be combined with bevacizumab to promote tumor regression. We previously showed that melanoma differentiation associated gene-7 (mda-7) protein exerts potent antitumor and antiangiogenic activity. Thus, in this study, we investigated the therapeutic effects of mda-7 in combination with bevacizumab using lung cancer as a model. In vitro, treatment of human umbilical vein endothelial cells with conditioned medium from Ad-mda7 plus bevacizumab-treated lung tumor cells showed reduced VEGF ligand-receptor binding, and decreased cell survival, resulting in growth arrest and apoptosis. In vivo, treatment of subcutaneous lung tumor xenografts with bevacizumab plus Ad-mda7 resulted in significant tumor growth inhibition and improved survival compared to tumor growth in control mice. Furthermore, tumors in all the Ad-mda7 plus bevacizumab-treated mice completely regressed, and these were tumor free through the study's end. Molecular analysis showed enhanced tumor cell apoptosis and reduced VEGF and CD31 expression in Ad-mda7 plus bevacizumab-treated tumors. Thus, Ad-mda7 and bevacizumab treatment produces a synergistic and complete therapeutic effect against human lung cancer.
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PMID:mda-7 In combination with bevacizumab treatment produces a synergistic and complete inhibitory effect on lung tumor xenograft. 1723 6

Breast cancer is the most frequent tumor of women. The development of effective adjuvant therapy based on postoperative administration of short-term chemotherapy (4-6 months) or long-term hormone therapy (5 years) or both, significantly improved survival of patients. However, therapy of adjuvant/metastatic disease is still palliative with a very low probability to induce complete remission and definitive cure of disease. The relevant efforts of basic research to identify the key and selective molecular alterations, which sustain breast cancer growth and progression allowed the possibility to develop specific molecular target treatments. Trastuzumab, a humanized monoclonal antibody to HER-2, is the first molecular targeting agent approved for therapy of metastatic breast cancer, capable to significantly improve clinical outcome in combination with cytotoxic therapy. Recent preliminary data from randomized, prospective, clinical trials suggest that trastuzumab decreases the risk of early recurrence by 50% in patients with HER-2-positive disease. Other novel targeted treatments are in clinical evaluation, including antiangiogenic compounds (Bevacizumab, sunitinib, vatalanib, and others) and bi-functional drugs such as lapatinib (anti Her-2 and EGFR agent) showing promising activity. This review provides an updated overview of the status of development of targeted therapy in breast cancer, as well as the challenges related to the rational use of molecular targeting agents.
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PMID:Targeted therapy of breast cancer. 1734 46

As targeted therapies for cancer become increasingly integrated into standard practice, appropriate selection of the patients most likely to benefit from these therapies is now receiving critical scrutiny. Early experience with therapies directed at targets that are definitively overactive (e.g. the bcr-abl tyrosine kinase targeted by imatinib) or over-expressed [e.g. the human epidermal growth factor receptor 2 (HER2) targeted by trastuzumab] has generated the perception that pre-treatment target assessment is a pre-requisite for therapy with all targeted agents. However, emerging evidence suggests that this is not presently feasible for anti-angiogenic agents. Despite considerable evidence for the association of intratumoral and/or plasma vascular endothelial growth factor (VEGF) levels with tumor progression and/or poor prognosis, pre-treatment VEGF levels do not appear to be predictive of response to anti-angiogenic therapy. This may possibly be due to the complexity of the angiogenic pathways and the limitations associated with current methods of VEGF detection and quantification; e.g. low assay sensitivity and lack of standardized methods could prevent detection of very small increases in VEGF, which may be clinically important in patients with tumors that are highly dependent on this growth factor. In addition to a general lack of agreement as to the relative clinical relevance of circulating versus tumor VEGF levels, the absence of a 'gold standard' VEGF detection assay and the lack of a predefined, clinically relevant cut-off pose a significant hindrance to the clinical utility of VEGF measurements for therapy selection. Given the fundamental importance of angiogenesis for tumor growth and progression, and the key role of VEGF in these processes, presently it seems appropriate to view anti-VEGF agents such as bevacizumab (Avastin) as having potential utility, independently of pre-treatment screening. Further research is needed to define the relationship between potential surrogate markers of VEGF pathway activity and clinical outcomes.
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PMID:Challenges for patient selection with VEGF inhibitors. 1737 72

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.
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PMID:The potential of antiangiogenic therapy in non-small cell lung cancer. 1740 76


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