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)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although modest survival benefit has been observed with surgery, radiotherapy and platinum-based chemotherapy, an efficacy plateau has been reached. It has become obvious, therefore, that additional treatments are needed in order to provide an improved survival benefit for these patients. The use of molecular targeted therapies, particularly those against tumor capillaries, has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is the first targeted drug that has shown survival advantage when combined with chemotherapy in NSCLC. Other antivascular agents, including vascular disrupting agents (VDAs) and different small-molecule receptor tyrosine kinase inhibitors, have also shown promise in phase I and II trials in NSCLC. The aim of this study is to describe the clinical properties of these drugs and to discuss the evidence that supports their use in the treatment of NSCLC. Furthermore, we plan to review the main pitfalls of antivascular strategies in NSCLC cancer therapy as well as assess the future direction of these treatment methods with an emphasis on clarifying the molecular background of the effects of these drugs and defining the biomarkers.
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PMID:Targeting blood vessels for the treatment of non-small cell lung cancer. 1869 Aug 45

In the past few years many encouraging advancements have been made in understanding the molecular mechanisms underlying carcinogenesis and tumor progression. These improvements have led to the identification of promising new targets for cancer therapy. There has been much success with the HER2 targeting antibody trastuzumab (Herceptin) in the treatment of early stage and metastatic breast cancer. Consequently, several antibodies inhibiting cellular signaling of VEGF and EGFR were tested with respect to their efficacy in breast cancer. In phase II and III clinical trials the humanized anti-VEGF antibody bevacizumab (Avastin) alone or in combination with capecitabine exhibited responses in patients with metastatic breast cancer. Recent developments focus on small molecules interfering with different signal transduction pathways in tumor cells. Numerous inhibitors of EGF and VEGF receptor tyrosine kinases and farnesyl transferases are in early stages of clinical development for breast cancer. Another promising approach is the targeting of endothelins and their two G-protein coupled receptors (ET(A)R und ET(B)R). In this article, we will shortly outline well established targeted treatments and discuss the current development of novel agents to be utilized for molecular targeted breast cancer therapy. Due to the heterogeneity of disease and varying response to conventional systemic therapies, these new perceptions may lead to substantial patient benefit and provide a promising basis for future clinical application.
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PMID:Targeted therapies in breast cancer: established drugs and recent developments. 1869 Aug 83

The ability of human tumor cell lines to produce various cytokines, chemokines, angiogenic and growth factors was investigated using Luminex multiplex technology. Media conditioned by tumor cells protected tumor cells from drug-induced apoptosis and stimulated tumor cell proliferation. Antibodies neutralizing IL-6, CXCL8, CCL2 and CCL5 blocked this stimulation. Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of IL-6, CXCL8, CCL2, CCL5, BFGF, G-CSF and VEGF. This stimulation was associated with drug-induced activation of NF-kappaB, AP-1, AP-2, CREB, HIF-1, STAT-1, STAT-3, STAT-5 and ATF-2 transcription factors and upregulation of IL-6, CXCL8, FGF-2, CSF-3 and CCL5 gene expression. Treatment of tumor cells with doxorubicin and antibodies neutralizing G-CSF, CCL2 or CCL5 had higher inhibitory effects than each modality used alone. These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug-mediated destruction. Clinical studies showed that antibodies neutralizing VEGF (Avastin/Bevacizumab) or blocking HER2/neu signaling (Herceptin/Trastuzumab) could increase the efficacy of chemotherapy, although these beneficial effects have been limited. It is possible that drug-stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy. In addition, numerous growth factors and chemokines share angiogenic and growth-stimulating properties, and thus reduction of a single factor is insufficient to completely block tumor growth. Thus, a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy.
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PMID:Chemotherapeutic drugs and human tumor cells cytokine network. 1869 97

We evaluate the effects of adjuvant treatment with the angiogenesis inhibitor Avastin (bevacizumab) on pathological tissue specimens of high-grade glioma. Tissue from five patients before and after treatment with Avastin was subjected to histological evaluation and compared to four control cases of glioma before and after similar treatment protocols not including bevacizumab. Clinical and radiographic data were reviewed. Histological analysis focused on microvessel density and vascular morphology, and expression patterns of vascular endothelial growth factor-A (VEGF-A) and the hematopoietic stem cell, mesenchymal, and cell motility markers CD34, smooth muscle actin, D2-40, and fascin. All patients with a decrease in microvessel density had a radiographic response, whereas no response was seen in the patients with increased microvessel density. Vascular morphology showed apparent "normalization" after Avastin treatment in two cases, with thin-walled and evenly distributed vessels. VEGF-A expression in tumor cells was increased in two cases and decreased in three and did not correlate with treatment response. There was a trend toward a relative increase of CD34, smooth muscle actin, D2-40, and fascin immunostaining following treatment with Avastin. Specimens from four patients with recurrent malignant gliomas before and after adjuvant treatment (not including bevacizumab) had features dissimilar from our study cases. We conclude that a change in vascular morphology can be observed following antiangiogenic treatment. There seems to be no correlation between VEGF-A expression and clinical parameters. While the phenomena we describe may not be specific to Avastin, they demonstrate the potential of tissue-based analysis for the discovery of clinically relevant treatment response biomarkers.
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PMID:High-grade glioma before and after treatment with radiation and Avastin: initial observations. 1877 28

Bevacizumab, a humanized anti-VEGF monoclonal antibody has shown promise in various clinical trials. We report the development and testing of Bi-213 (an alpha-emitting radionuclide) labeled bevacizumab for in vitro and in vivo studies using two different chelators viz cDTPA and CHX-A''. The developed labeling method showed high labeling yields of 93.6% and 89.7% for cDTPA and CHX-A'' respectively and the results were reproducible. The in vitro and in vivo stability tests were carried out using Bi-213 and long half-life Bismuth isotope (Bi-205/Bi-206) for pharmacokinetics. The in vitro results showed remarkable stability of the radiolabeled bevacizumab regardless of the chelator. The in vivo pharmacokinetics studies however, showed that the uptake and retention of cDTPA-bevacizumab was significantly higher in kidneys (p-value 0.02) and lower in liver and spleen (p-value <0.0001 and 0.0009 respectively). The values for the two conjugates compared well in blood but the longer term data for CHX-A'' conjugate showed slow clearance resulting in a significantly longer blood half-life of the product (211 hours compared to 4 hours for cDTPA-bevacizumab). Preliminary in vivo results showed increased efficacy of the combination therapy compared to bevacizumab only. The tumor area (mm(2)) decreased from 24.8 +/- 3.6 and 12.8 +/- 1.7 for 1 and 3 mg/kg cold bevacizumab only to 6.5 +/- 0.7 and 7.5 +/- 4.8 when single dose of 333 MBq/kg of (213)Bi-bevacizumab was administered as combination therapy. In conclusion it can be said that stable radiolabeled bevacizumab conjugates can be prepared with Bi-213 with either chelators used. The shorter blood half-life with cDTPA-bevacizumab may not be a major concern with Bi-213 as its own half-life is 46 minutes only. The combination therapy proved superior to bevacizumab alone therapy, a phenomenon that can be particularly useful in cancers where bevacizumab alone has shown limited success like prostate cancer.
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PMID:Preparation and testing of bevacizumab radioimmunoconjugates with Bismuth-213 and Bismuth-205/Bismuth-206. 1870 62

Aberrant stimulation of the canonical Wnt pathway induces mammary tumorigenesis in mice. It has been well documented that two types of tumors, adenocarcinoma and adenocarcinoma with squamous metaplasia, develop in these mutants. However, the molecular mechanism underlying the induction of squamous transdifferentiation remains largely unknown. Here, we show that JNK/SAPK signaling plays an important role in Wnt-dependent mammary development and malignant transformation. The JNK/SAPK pathway is stimulated in pregnancy-mediated lobulo-alveolar morphogenesis, a process highly dependent on Wnt/beta-catenin signaling. Strong elevations of JNK/SAPK signaling are associated with squamous metaplasia of the Wnt-induced adenocarcinoma. Reconstitution of beta-catenin and JNK/SAPK signaling activities also promotes expression of the squamous cell marker in cultured epithelial cells. Furthermore, a synergistic activation of these two pathways can be identified in the malignant squamous cells of human endometrial and lung cancers. This is potentially a significant discovery in modern cancer therapy because of the effectiveness of an angiogenesis inhibitor, Avastin, for the treatment of adenocarcinoma, but not squamous cell carcinoma, in human lung cancers. Our finding may improve the usage of biomarkers to distinguish these two poorly differentiated tumor types, sharing similar histologic features.
Neoplasia 2008 Sep
PMID:Co-opted JNK/SAPK signaling in Wnt/beta-catenin-induced tumorigenesis. 1871 62

Breast cancer is the most common malignancy in women worldwide, and represents the leading cause of death in the female population. Incidence of breast cancer increases with age, and older patients are more likely to have disseminated disease at diagnosis. For those patients who relapse after endocrine treatment or in which the tumor does not express hormone receptors, chemotherapy should be considered. Single agent sequential regimens should be preferred to combination regimens, which are usually more toxic and provide a limited survival gain. New drugs which have proven efficacy against metastatic breast cancer are Taxanes (Paclitaxel and Docetaxel), Vinorelbine, Capecitabine, Gemcitabine, various and newer formulations of Anthracyclines (Epirubicin, oral Idarubicin, liposomal Doxorubicin). The anti-HER2 monoclonal antibody Trastuzumab in association with chemotherapy can be administered to elderly patients who present with HER2 overexpressing tumors, though cardiac monitoring is necessary due to cardiac adverse events. Bevacizumab, an anti-VEGF monoclonal antibody, was recently patented and approved in combination with Paclitaxel for the treatment of metastatic breast cancer. Globally, there is need to develop therapeutics able to circumvent resistance against hormonal and other therapies for advanced breast cancer, which are expected to be safe and effective in this age class.
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PMID:Chemotherapy and targeted agents for elderly women with advanced breast cancer. 1899 87

Following the clinical success of Bevacizumab, a humanized monoclonal antibody that affects the interaction between vascular endothelial growth factor (VEGF) and its receptors, blocking tumor-induced angiogenesis has become one of the most important targets for the development of new cancer therapeutic drugs and procedures. Among the latter, therapeutic vaccination using VEGF as antigen presents itself as very attractive, with the potential of generating not only a growth factor blocking antibody response but also a cellular response against tumor cells and stromal elements, which appear to be a major source of tumor VEGF. In this paper, we report the development of a protein vaccine candidate, based on a human modified VEGF antigen that is expressed at high levels in E. coli. With respect to controls, immunization experiments in C57BL/6 mice using weekly doses of this antigen and three adjuvants of different chemical natures show that time for tumor development after subcutaneous injection of Melanoma B16-F10 cells increases, tumors that develop grow slower, and overall animal survival is higher. Immunization also prevents tumor development in some mice, making them resistant to second tumor challenges. Vaccination of mice with the human modified VEGF recombinant antigen produces antibodies against the human antigen and the homologous mouse VEGF molecule. We also show that sera from immunized mice block human VEGF-induced HUVEC proliferation. Finally, a possible contribution of T cell cytotoxicity to the overall anti-tumor effect is suggested from the results of vaccination experiments where CD8+ lymphocytes were impaired using neutralizing rat antibodies.
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PMID:Anti-tumoral effect of active immunotherapy in C57BL/6 mice using a recombinant human VEGF protein as antigen and three chemically unrelated adjuvants. 1903 78

Angiogenesis plays a major role in the pathogenesis of many disorders. Vascular endothelial growth factor has been shown to be the key regulator of normal and pathological angiogenesis. Increased expression of VEGF has been associated with tumor neovascularization, metastasis and proliferation of cancer cells. Bevacizumab, a monoclonal antibody against VEGF, has shown promising preclinical and clinical activity against different types of cancer, particularly in combination with chemotherapy. There is an increasing evidence that bevacizumab has a disease-modifying effect in metastatic colorectal carcinoma (CRC), and also in advanced hepatocellular carcinoma. Further investigation is needed to evaluate the role of antiangiogenic therapeutic strategies in other gastrointestinal malignancies. This review summarizes recent knowledge about antiangiogenic therapy for gastrointestinal cancers.
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PMID:[Antiangiogenic therapy for gastrointestinal tumors]. 1904 83

Angiogenesis is a complex process which is critical for the growth, invasion, and metastasis of tumors. In the past ten years numerous new agents have been developed as angiogenesis inhibitors. Angiogenesis inhibitors can be classified by their targeted area of the angiogenic process; (1) VEGF and its receptors VEGFR (e.g. Bevacizumab); (2) tyrosine kinases within endothelial cells (Sunitinib); (3) proliferation of endothelial cells (Endostatin); (4) MMPs (Marimastat); (5) intercellular interactions via integrins (Cilengitide) and (6) combinations of the above mechanisms (Thalidomide). Some showed anti-tumor effects with objective responses and stable disease, and some disappeared from clinical use due to unexpected side effects or insufficient efficacies. Further investigations of combined therapies including angiogenesis inhibitors will shed light on the treatment of advanced and metastasized malignancies.
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PMID:Clinical approaches toward tumor angiogenesis: past, present and future. 1912 35


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