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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic adenocarcinoma is a leading cause of cancer death in the United States and represents a challenging chemotherapeutic problem. The treatment of advanced pancreatic cancer with gemcitabine has only modest activity with a small survival benefit, and toxicity continues to be a major obstacle. New therapeutic strategies that notably lack cross resistance with established treatment regimens are much needed in pancreatic cancer. One such approach is the pharmacological control of angiogenesis that represents a novel approach to the management of pancreas cancer, since the pathological development of vascular supply is a critical step for tumor growth and may affect its prognosis. Since pancreatic carcinoma show strong tumor neoangiogenesis, overexpression of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, in pancreatic cancer and consequently are highly vascularized, the role of anti-angiogenic therapies is under exploration at present. Hence, this review covers the summary of the development of anti-angiogenesis as anti-antitumor therapy in pancreatic carcinoma, including matrix-metalloproteinase inhibitors (MMPIs), such as marimastat and BAY 12-9566, anti-VEGF agent, bevacizumab (Avastin, Genentech, South San Francisco, CA, USA), celecoxib (a cyclooxygenase-2 inhibitor), thalidomide and others. Role of markers of angiogenesis in predicting response to therapy is also discussed.
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PMID:Anti-angiogenesis therapy in pancreatic carcinoma. 1652

The goal of the current study was to determine if the antiangiogenic drug Avastin would improve the effectiveness of Photodynamic Therapy (PDT) in a xenograft model of Kaposi's sarcoma (KS). Human KS-Imm tumors transplanted in nude mice were treated with Photofrin-mediated PDT. Expression parameters of proangiogenic molecules were documented and the tumoricidal effectiveness of PDT combined with the VEGF inhibitor Avastin was determined. PDT induced increased expression of HIF-1alpha, VEGF, PGE2, TNF-alpha, and IL-1beta within treated KS tumor tissue. Significant overexpression of KS cell derived human VEGF and to a lesser extent overexpression of host cell derived mouse VEGF were detected within treated tumors. Combining PDT with Avastin resulted in a significant increase in the long-term responsiveness of treated KS tumors when compared to individual treatments. These results demonstrate for the first time that Avastin can improve PDT treatment effectiveness and suggest that VEGF inhibitors may ameliorate the clinical efficacy of PDT.
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PMID:Avastin enhances photodynamic therapy treatment of Kaposi's sarcoma in a mouse tumor model. 1656 22

Chronic inflammation is a well-known risk factor for cancer. Proinflammatory mediators such as prostaglandin E2 (PGE2) promote colorectal tumor growth by stimulating angiogenesis, cell invasion, and cell growth, and inhibiting apoptosis. Molecules that regulate tumor-associated angiogenesis provide promising therapeutic targets for treatment of colorectal cancer (CRC) as indicated by the recent development of the novel anti-angiogenic agent bevacizumab (Avastin). However, use of this drug only prolongs survival by several months, highlighting the importance of finding more effective treatment regimens. We report here that PGE2 induces expression of CXCL1 (growth-regulated oncogene alpha), a pro-angiogenic chemokine, in human CRC cells. More importantly, CXCL1 released from carcinoma cells induces microvascular endothelial cell migration and tube formation in vitro. Furthermore, PGE2 promotes tumor growth in vivo by induction of CXCL1 expression, which results in increased tumor microvessel formation. These results have potential clinical significance because we found that CXCL1 expression correlates with PGE2 levels in human CRCs. Collectively, our findings show for the first time that CXCL1 is regulated by PGE2 and indicate that CXCL1 inhibitors should be evaluated further as potential anti-angiogenic agents for treatment of CRC.
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PMID:CXCL1 induced by prostaglandin E2 promotes angiogenesis in colorectal cancer. 1656 91

Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the "humanization of antibodie" or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies "armed" with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.
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PMID:Monoclonal and bispecific antibodies as novel therapeutics. 1664 69

Advances in chemotherapeutic agents have led to improved outcomes for patients with metastatic colorectal cancer (CRC). Chemotherapies, however, are limited by their toxicities and lack of specificity. Aberrations in the regulation and expression of growth factors have been implicated in the development of CRC, and this understanding has led to the development of targeted agents. In 2004, two novel agents, bevacizumab and cetuximab, were approved by the US Food and Drug Administration for the treatment of metastatic CRC. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, and cetuximab, a human-mouse chimeric monoclonal antibody to the epidermal growth factor receptor, have changed the field dramatically. Bevacizumab appears to augment the efficacy of combination chemotherapy regimens for the treatment of metastatic CRC in both the first- and second-line settings, and the role of bevacizumab as part of adjuvant treatment is the subject of ongoing trials. However, because of the increased incidence of serious arterial thromboembolic events, gastrointestinal perforations, bleeding complications, and hypertension associated with bevacizumab, this agent is probably not indicated in all circumstances. Combination treatment with cetuximab and irinotecan appears appropriate in patients with advanced CRC who have failed irinotecan. Patients who are unable to receive additional irinotecan may be treated with cetuximab monotherapy. Positive epidermal growth factor receptor status by immunohistochemistry of a tumor specimen is presently mandated to determine candidacy for this therapy, although this assay appears to be suboptimal and newer assessment techniques to determine suitability for therapy must be developed. Phase III trials should shed light on the role of cetuximab in the first-line metastatic and adjuvant settings. Multitargeted strategies in CRC combining chemotherapy with bevacizumab and cetuximab are currently being explored. Further advances in the treatment of CRC are expected through continued scientific investigation and well-designed clinical trials.
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PMID:Targeted therapy in colorectal cancer. 1672 21

Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF-A). Non-Hodgkin's lymphoma patients with high serum VEGF levels have an inferior survival compared to patients with low VEGF levels. Bevacizumab was administered through a central line at 15 mg kg(-1) IV on day 1 followed by rituximab (R) and CHOP on day 2 for cycle 1 and day 1 for cycles 2 - 8. Serum levels of bevacizumab and R were measured at specified time points to assess pharmacokinetics (PK). Plasma and urine samples were also analysed for VEGF. Tumor samples were stained for VEGF, CD31 and factor VIII by immunohistochemistry. Thirteen patients with newly-diagnosed DLBCL received a total of 88 cycles (range 2 - 8, median 7). Best response included five CR, six PR, one SD and one PD with an overall response rate of 85% and complete response rate of 38%. The 12-month PFS is 77% and a median follow-up of 16.9 months for the surviving patients. All tumor samples stained strongly positive for VEGF and there was a marginal association between baseline plasma VEGF and response (p = 0.04). Patients with higher plasma VEGF levels were generally younger and had bulky disease. Micro-vessel density did not correlate with presenting disease characteristics, VEGF expression or response. The PK of bevacizumab and rituximab were not influenced by combined treatment. In this patient population, treatment with RA-CHOP did not result in any episodes of grade 3 or 4 proteinuria, heart failure or hemorrhage. The RA-CHOP combination was generally well tolerated and safe.
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PMID:Rituximab, bevacizumab and CHOP (RA-CHOP) in untreated diffuse large B-cell lymphoma: safety, biomarker and pharmacokinetic analysis. 1684 Jan 82

Angiogenesis and neovascularization are important mechanisms for tumor growth, progression and, subsequent metastasis. Cancer cells, as part of an inflammatory process, produce and induce multiple molecules (proangiogenic and antiangiogenic) from the surrounding stromal cells. Vascular Endothelial Growth Factor (VEGF) is the most relevant proangiogenic molecule among them. Many inhibitors of angiogenesis have been developed in the last years with the aim to block the tumor blood supply as a new anticancer strategy. Bevacizumab, an anti-VEGF, has been already approved for its use in colorectal cancer showing prolonged disease free survival as well as overall survival. It shows also important activity in breast, lung, ovarian and kidney cancer. Many others inhibitors are in advanced clinical development and show promising results as well. Current basic and clinical research in this field is generating great expectations for the future of cancer treatment.
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PMID:Inhibitors of angiogenesis. 1687 May 37

CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.
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PMID:CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo. 1689 55

The mainstay of any curative treatment in renal cell carcinoma (RCC) is surgery. In the case of metastatic disease at presentation, a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment. Interferon (IFN)-a offers in a small but significant percentage of patients advantage in overall survival. Interleukin (IL)-2-based therapy gives similar survival rates. To date, hormonal therapy and chemotherapy do not have a proven impact on survival. Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel-Lindau (VHL) gene. This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor (VEGF) in this highly vascularized tumor. This opens interesting new treatment strategies including blockade of VEGF with the monoclonal antibody bevacizumab (Avastin) and inhibition of VEGF receptor tyrosine kinases with small oral molecules such as sunitinib (SU11248, Sutent) or PTK787. Likewise, inhibition of the Raf kinase pathway with oral sorafenib (Bay 43-9006, Nexavar) or inhibition of the mTOR pathway with intravenous CCI-779 are under investigation. Preliminary clinical results with all these compounds are promising, and the results of ongoing first-line phase III studies will become available in the next years.
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PMID:Targeted approaches for treating advanced clear cell renal carcinoma. 1697 18

Neuroblastoma (NB) is a rapidly growing, well-vascularized childhood cancer that often presents with metastases. The overall five-year survival in NB is approximately 45% despite multimodality treatment, and therefore there is a clinical need for new therapeutic strategies. NB frequently overexpresses the angiogenic factor VEGF (vascular endothelial growth factor). The aim of this study was to investigate the effect of bevacizumab (Avastin, Genentech/Roche), a humanized anti-VEGF-A antibody, on NB growth in three different xenograft models, chosen to resemble high-risk NB. The human NB cell lines SK-N-AS, IMR-32 and SH-SY5Y, which are poorly differentiated and overexpress VEGF-A, were injected s.c. in immunodeficient mice. Bevacizumab was given intraperitoneally twice weekly at 5 mg/kg body weight, starting at a tumor volume of 0.3 mL. Bevacizumab significantly (p < 0.01-0.05) reduced NB growth in vivo without toxicity by causing a 30-63% reduction of angiogenesis, but had no effect on NB cell survival in vitro. Serum concentrations of VEGF-A increased two- to six-fold during bevacizumab therapy which did not result in faster tumor growth compared with control animals. Based on our experimental data we suggest consideration of bevacizumab in treatment of high-risk NB that does not respond to conventional therapy and that overexpresses VEGF.
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PMID:The anti-VEGF antibody bevacizumab potently reduces the growth rate of high-risk neuroblastoma xenografts. 1698 84


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