Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent approval of bevacizumab (Avastin), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with chemotherapy for the treatment of patients with metastatic colorectal cancer, has provided proof of principle of the efficacy of antiangiogenic strategies for cancer therapy. The activity of bevacizumab is primarily attributed to its ability to inhibit endothelial cell survival. Whether anti-VEGF strategies may also have a direct effect on cancer cell survival is poorly understood. We show that serum-starved colon cancer cells differentially respond to autocrine production of VEGF with the induction of hypoxia inducible factor-1 alpha (HIF-1 alpha) and survival under hypoxic conditions. Inhibition of VEGF or VEGF receptor 2 (VEGFR2)/KDR, but not VEGFR1/Flt-1, was sufficient to abrogate VEGF-mediated induction of HIF-1 alpha and survival in sensitive HCT116, but not in resistant HT29, colon cancer cells. These results provide evidence that a VEGF/KDR/HIF-1 alpha autocrine loop differentially mediates survival of hypoxic colon cancer cells, and they suggest that colon cancer cells may be intrinsically sensitive or resistant to anti-VEGF strategies, which may determine the therapeutic efficacy of bevacizumab.
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PMID:Differential involvement of vascular endothelial growth factor in the survival of hypoxic colon cancer cells. 1817 21

Bevacizumab, an anti-vascular endothelial growth factor (VEGF-A) antibody, is used in metastatic colorectal carcinoma (CRC) treatment, but responses are unpredictable. Vascular endothelial growth factor is alternatively spliced to form proangiogenic VEGF(165) and antiangiogenic VEGF(165)b. Using isoform-specific enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, we found that over 90% of the VEGF in normal colonic tissue was VEGF(xxx)b, but there was a variable upregulation of VEGF(xxx) and downregulation of VEGF(xxx)b in paired human CRC samples. Furthermore, cultured colonic adenoma cells expressed predominantly VEGF(xxx)b, whereas colonic carcinoma cells expressed predominantly VEGF(xxx). However, adenoma cells exposed to hypoxia switched their expression from predominantly VEGF(xxx)b to predominantly VEGF(xxx). VEGF(165)b overexpression in LS174t colon cancer cells inhibited colon carcinoma growth in mouse xenograft models. Western blotting and surface plasmon resonance showed that VEGF(165)b bound to bevacizumab with similar affinity as VEGF(165). However, although bevacizumab effectively inhibited the rapid growth of colon carcinomas expressing VEGF(165), it did not affect the slower growth of tumours from colonic carcinoma cells expressing VEGF(165)b. Both bevacizumab and anti-VEGF(165)b-specific antibodies were cytotoxic to colonic epithelial cells, but less so to colonic carcinoma cells. These results show that the balance of antiangiogenic to proangiogenic isoforms switches to a variable extent in CRC, regulates tumour growth rates and affects the sensitivity of tumours to bevacizumab by competitive binding. Together with the identification of an autocrine cytoprotective role for VEGF(165)b in colonic epithelial cells, these results indicate that bevacizumab treatment of human CRC may depend upon this balance of VEGF isoforms.
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PMID:VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. 1834 29

Bevacizumab is the fi rst vascular endothelial growth factor-targeted agent shown to increase survival in patients receiving first- and second-line intravenous 5-FU-based chemotherapy for the treatment of metastatic colorectal cancer. Bevacizumab is typically well tolerated and its major side effects include hypertension, proteinuria, bleeding, gastrointestinal perforation and arterial thrombotic events. Although exfoliative dermatitis has been described as a side effect in 19% of patients, skin rash (type unspecified) has rarely been described in patients following infusion of bevacizumab. We recently reported the fi rst patient with colon cancer manifesting a correlation between rash and a positive drug response with bevacizumab. A 49-year old male with T3 N1 M1 rectal carcinoma received modified FOLFOX-6/bevacizumab, which he tolerated very well except for grade 2 skin rash related to bevacizumab. The rash continued to progress as the serum carcinoembryonic antigen decreased significantly. Computed tomography and positron emission tomography scan confirmed response to FOLFOX/bevacizumab. We therefore believe that this rash was linked to bevacizumab administration and correlated with response to therapy. Grade 1/2 rash has been described in patients after infusion of bevacizumab in initial phase I and II studies. Skin rash was observed in 34% and 46% of patients in the Kabbinavar's study receiving 5 mg/kg dose and 10 mg/kg respectively but no patient developed > grade 3 rash. This toxicity was not well described in pivotal phase III studies. On the other hand, acneiform rash occurs in > 90% patients who receive cetuximab and panitumumab, severity of which appears to be predictive of response. To our knowledge, this case report is the second report of possible correlation between rash and a positive drug response associated with bevacizumab and warrants further investigation of similar observation.
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PMID:Correlation between rash and a positive drug response associated with bevacizumab in a patient with advanced colorectal cancer. 1850 Oct 75

Pharmacotherapeutic decisions are increasingly constrained in all clinical settings by the costs of drug treatment and medical care. Some biotech therapies (e.g., Avastin, Cerzyme, Herceptin, Gleevec, Erbitux) can cost from $10,000 to more than $100,000 per treatment episode. In 1996 the average drug treatment cost for advanced colon cancer was $500, and the average patient survival was 11 months. In 2006 the average drug treatment cost for such patients was $250,000, and the average patient survival was 24 months.(1) It is apparent that we are quickly arriving at a situation in which the determinants of medical decision making are not simply the clinical risks and benefits of treatment options but also how these are balanced against the economic costs of therapy.
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PMID:Using pharmacoeconomics to value pharmacotherapy. 1867 82

Colorectal cancer treatment has experienced important advances in the last 5 years. New targeted therapies have been included in the classical regimens based on 5-fluorouracil, oxaliplatin, or irinotecan. This new approach has brought great revolution in the treatment of this type of cancer. Bevacizumab (Avastin), a new antivascular endothelial growth factor drug, has been shown to improve overall survival in combination with chemotherapy in first-line and second-line settings as compared with standard chemotherapy regimens alone. This case report demonstrates our experience with bevacizumab in a colon cancer patient with liver, lung, and regional lymph node metastases who had a relapse in the liver after adjuvant treatment with capecitabine (Xeloda). The addition of bevacizumab to the FOLFOX4 regimen resulted in a partial response that provided an opportunity for salvage hepatic surgery.
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PMID:The combination of FOLFOX4 and bevacizumab may enable salvage surgery of unresectable liver metastases in colon cancer. 1935 9

The introduction of novel agents targeted to specific molecular features of cancer cells promises more options and marked improvements in efficacy for treatment of colon cancer. This overview of clinical studies describes the effects of administering the targeted agents bevacizumab, cetuximab, and panitumumab, also known as monoclonal antibodies, to treat metastatic colorectal cancer (mCRC) patients. All three targeted agents have been approved for use by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products. Bevacizumab has been shown to extend survival when used in combination with irinotecan and 5-fluorouracil-based chemotherapy, and the addition of cetuximab to irinotecan and 5-fluorouracil-based chemotherapy overcomes irinotecan resistance. Cetuximab and panitumumab are both efficacious among refractory mCRC patients with wild-type KRAS tumors. Other targeted agents, for example, the tyrosine kinase inhibitors erlotinib, gefitinib, sunitinib, and vatalanib (PTK787/ZK 222584), are currently in various stages of clinical development.
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PMID:Chemotherapy with targeted agents for the treatment of metastatic colorectal cancer. 1941 18

It has been suggested that immunosuppressive cytokines such as transforming growth factor beta (TGF-beta) and interleukin 10 play an important role in the induction and/or maintenance of regulatory T-cells (Tregs) in patients with cancer. In the present study, whether or not vascular endothelial growth factor (VEGF) contributes to the induction and/or maintenance of Tregs was examined, because of experience with a patient in whom a positive correlation between VEGF concentration and the percentage of Tregs (% Tregs) among the total CD4(+) T-cells in the pleural effusion was found during dendritic cell activated lymphocyte therapy. CD4(+)CD25(high) T-cells were estimated as Tregs in the present study. In an in vitro experimental system, VEGF-containing malignant effusions increased the % Tregs in autologous peripheral blood mononuclear cells (PBMCs), which could be suppressed by the addition of a humanized monoclonal anti-VEGF antibody (bevacizumab [Avastin]). When VEGF-producing hepatic carcinoma cells were mix-cultured with PBMCs, the % Tregs increased and this increase was also suppressed by the addition of bevacizumab. Whether or not bevacizumab can affect the % Tregs of PBMCs in patients with colon cancer was also examined. Three out of four patients showed a significant decrease of the % Tregs after intravenous injection of bevacizumab. Interestingly, the expression of VEGF receptor-2 (VEGFR-2) was higher in Tregs than in other CD4(+) T-cells. Taken together, the data presented here indicate a contribution of VEGF to induction and/or maintenance of Tregs in patients with cancer.
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PMID:The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. 1941 23

Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), and it has shown promise as a clinical agent against metastatic colorectal cancer, and particularly in combination with chemotherapy. Bowel perforation is a known risk that's associated with bevacizumab use, but the etiology is unknown. Here we report on two cases of metastatic colorectal cancer in which the patients suffered from intestinal perforation after chemotherapy with bevacizumab. For the first case, a 47 year-old man had rectal cancer with concurrent liver and lung metastasis. He underwent chemotherapy with 5-fluorouracil, irinotecan and bevacizumab. Fever and abdominal pain developed seven days later, and rectal perforation was identified upon exploration 13 days later. For the second case, a 48 year-old woman had sigmoid colon cancer with peritoneal and ovary metastases. After seven days of chemotherapy with 5-fluorouracil, oxaliplatin and bevacizumab, exploratory surgery revealed a perforation at the ileum.
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PMID:Intestinal perforation in colorectal cancers treated with bevacizumab (Avastin). 1968 63

Overexpression of vascular endothelial growth factor (VEGF) by tumor cells promotes angiogenesis, which correlates with progressive tumor growth and poor outcomes in many types of cancer. Bevacizumab inhibits VEGF to promote regression of tumor vessels by limiting blood supply and tumor growth, enhancing delivery of chemotherapy, and inhibiting formation of new vessels. Combined with chemotherapy, bevacizumab prolongs progression-free and overall survival over chemotherapy alone in patients with metastatic carcinoma of the colon and rectum; unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC); and metastatic HER2-negative breast cancers (mBC). Side effects, including hypertension, proteinuria, bleeding, arterial thrombotic events, and impaired wound healing, can be clinically significant, particularly in patients with risk factors. To optimize patient outcomes, nurses should understand bevacizumab's role in cancer therapy, recognize symptoms of toxicity, and manage its side effects. This article describes the rationale for bevacizumab in the treatment of metastatic colorectal cancer, NSCLC, and mBC and discusses patient selection, treatment duration, and side-effect management to support the role of oncology nurses in caring for, educating, and enhancing treatment adherence among patients with cancer receiving bevacizumab. Two case studies are presented as examples of the complex scenarios nurses may encounter regarding these issues.
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PMID:Oncology nursing in a new era: optimizing treatment with bevacizumab. 1979 13

Options for the adjuvant therapy of resected stage III colon cancer have expanded beyond the previously well-accepted standard of 5-fluorouracil (5-FU) combined with leucovorin. The Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study confirmed that capecitabine (Xeloda) is at least as effective and is less toxic than a bolus 5-FU and leucovorin regimen for patients with stage III colon cancer. This study, in addition to National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06, which demonstrated the equivalence of tegafur-uracil (UFT)/leucovorin with 5-FU/leucovorin, provides support for use of oral fluoropyrimidines for adjuvant therapy. Support for use of multiagent chemotherapy has been provided by the European MOSAIC study, which demonstrated a significant improvement in 3-year disease-free survival for the addition of oxaliplatin (Eloxatin) to infusional 5-FU and leucovorin (FOLFOX). Although adding irinotecan (Camptosar) to a bolus 5-FU and leucovorin regimen did not improve outcome in the adjuvant setting, the PETACC studies are evaluating the combination of infusional 5-FU, leucovorin, and irinotecan. In contrast to agreement on the appropriateness of therapy for stage III colon cancer, adjuvant therapy for patients with stage II disease remains controversial. Future advances in adjuvant therapy may include targeted therapies. Based on data demonstrating efficacy for the monoclonal antibodies bevacizumab (Avastin) and cetuximab (Erbitux) in the metastatic setting, clinical trials adding these agents to standard chemotherapy have been initiated in the adjuvant setting. Specifically, one U.S. cooperative group trial will evaluate the addition of bevacizumab to chemotherapy, a second will assess the addition of cetuximab, and a third trial will evaluate FOLFOX, infusional 5-FU/leucovorin (FOLFIRI), and FOLFOX followed by FOLFIRI. Finally, a study for patients with stage II disease and adverse prognostic factors will open. An important consideration in the new clinical trials is an assessment of molecular markers that either predict response or resistance to therapy or provide other prognostic information.
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PMID:Adjuvant therapy of colon cancer: current status and future developments. 2001 5


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