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

Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice.
 ...
PMID:Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. 1844 98

Statins, HMG-CoA reductase inhibitors could be associated with the risk reduction of colorectal cancer. We previously demonstrated that simvastatin inhibits NF-kappaB signaling in human intestinal epithelial cells and ameliorates acute murine colitis. The aim of our study was to evaluate the effects of simvastatin on the apoptotic pathways related to NF-kappaB signaling in colon cancer cells, and on anticancer effects in 2 different animal models. We treated cell lines (COLO 205 and HCT 116) with simvastatin or vehicle and determined apoptosis by cell cycle analysis, Annexin V-FITC staining, caspase-3 activity assay and confocal microscopy. We assessed the expression of antiapoptotic factors by RT-PCR and Western blotting. In the colitis-associated colon cancer (CAC) model, we induced colonic tumors in C57/BL6 mice by azoxymethane and dextran sulfate sodium administration, and evaluated simvastatin's effect on tumor growth. In the xenograft model, we evaluated its effect on the inoculated tumor growth. In both cell lines, simvastatin caused dose- and time-dependent cell death. Annexin V staining significantly increased after simvastatin treatment. It augmented caspase-3 activity and downregulated the expression of Bcl-2, Bcl-xL, cIAP1 and cFLIP. In the CAC model, simvastatin significantly reduced tumor development. In the xenograft model, tumors from animals treated with simvastatin had smaller volumes, larger necrotic areas, lower expression of VEGF and higher apoptotic scores. In conclusion, simvastatin inhibited colon cancer development by induction of apoptosis and suppression of angiogenesis. These results suggest that simvastatin could be a potential chemopreventive and therapeutic agent of CAC as well as de novo colon cancer.
 ...
PMID:Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. 1852 6

We evaluated the efficacy of anti-human VEGF antibody (bevacizumab) with or without irinotecan (CPT-11) against lung metastases in which neovascularization was already induced, as a postoperative adjuvant therapy using orthotopically implanted colon cancer in rat. The high VEGF productive KM12SM human colon cancer cells were injected into the cecal wall. At 5 weeks after the injection, the cecum was removed including the tumor. Then, 5 mg/kg of bevacizumab and 40 mg/kg of CPT-11 were administered, alone or in combination, intravenously once a week for 3 weeks, from day 15 after the cecal removal. The results show that the incidences of macroscopic and/or microscopic lung metastases in the bevacizumab-alone group (B) and in the combination group (C) were significantly lower (B, p=0.001 and C, p=0.037) than that in the control group at day 35 after the cecal removal. The number of lung metastases in B was 0.8+/-0.8 (p=0.024) and in C 2.4+/-1.8 (p=0.060), each value lower than the 12.4+/-4.2 of the control group. The growth of a subcutaneously implanted tumor was significantly inhibited in the combination group compared to either the CPT-alone (p=0.003) or the bevacizumab-alone groups (p=0.027). Apoptosis was significantly (p<0.001) induced in the combination group. In conclusion, a beneficial effect of bevacizumab against postoperative lung metastases may be expected even after the establishment of neovascularization in metastatic foci in nude rat. The results from the present subcutaneously implanted tumor model suggested that a higher efficacy may be expected when bevacizumab is combined with the cytotoxic agent CPT-11, compared to bevacizumab alone, against tumors with a variety of VEGF production levels in clinical situations.
 ...
PMID:Efficacy of the combined use of bevacizumab and irinotecan as a postoperative adjuvant chemotherapy in colon carcinoma. 1869

Several lines of evidence support an important role of TGF-beta in the development of colorectal cancer, although the molecular consequences are largely unknown. Soluble transforming growth factor-beta receptor type II (sTbetaRII) is a target of transforming growth factors-beta (TGF-beta) that plays an important role in regulation tumorigenesis, angiogenesis and metastasis of cancer. To elucidate whether overexpression of sTbetaRII could antagonize TGF-beta in colon cancer cells, we constructed a plasmid that contains a cDNA encoding human extracellular region of TbetaRII and transfected this construction into LoVo cells. Surprisingly, in the absence of TGF-beta1, the overexpression of sTbetaRII antagonized TGF-beta-induced cell proliferation, invasion, motility and angiogenesis, and decreased expression of VEGF and MMP-9. Also, sTbetaRII inhibited TGF-beta-induced apoptosis and improved the induction of antitumor immunity. Our data indicated that sTbetaRII attenuated the biological activities of TGF-beta, suggesting that sTbetaRII may have a therapeutic benefit in colorectal cancer.
 ...
PMID:Soluble transforming growth factor beta type II receptor attenuates TGF-beta1 activity in human colorectal cancer LoVo cells. 1902 Jul 27

Hypoxia-inducible factor (HIF)-1 and HIF-2 are heterodimeric transcription factors that mediate the cellular response to hypoxia. Their key regulatory subunits, HIF-1alpha and HIF-2alpha, are induced similarly by hypoxia, but their functional roles in cancer may be distinct and isoform-specific. SW480 colon cancer cells with stable expression of siRNA to HIF-1alpha or HIF-2alpha or both were established. HIF-1alpha-deficient cells displayed lower rates of proliferation and migration, but HIF-2alpha-deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF-1alpha deficiency inhibited overall tumor growth, whereas deficiency of HIF-2alpha stimulated tumor growth. In human colon cancer tissues, expression of HIF-1alpha and to a lesser extent, HIF-2alpha, was linked to upregulation of VEGF and tumor angiogenesis. However, loss of expression of HIF-2alpha but not HIF-1alpha was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF-1alpha and HIF-2alpha target genes that may explain these phenotypic differences. Collectively, these findings suggest that HIF isoforms may have differing cellular functions in colon cancer. In particular, HIF-1alpha promoted the growth of SW480 colon cancer cells but HIF-2alpha appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties.
 ...
PMID:HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. 1903 Jan 86

Considerable progress has been made in the treatment of colon cancer from the era when 5-fluorouracil was the only effective agent for this disease. In addition to new chemotherapeutic agents, such as oxaliplatin, irinotecan, and capecitabine, the advent of biologic agents has contributed considerably to the treatment of colon cancer and has improved outcomes. An increased understanding of cancer at the molecular and genetic level has allowed for the development of therapeutics that target the multiple pathways essential to malignant behavior. While currently approved biotherapy in advanced colon cancer is limited to monoclonal antibodies against VEGF and EGFR, many more biologics targeting different pathways of oncogenesis are in development. There is also great interest in combining biotherapy not only with chemotherapy, but also with other biologics. Using rational combination biotherapy could overcome mechanisms of cancer cell resistance and result in synergistic activity. We review the various molecular targets of biologic therapy in colon cancer, discuss the rationale for their use as single agents and in combination, and present clinical evidence demonstrating their efficacy.
 ...
PMID:Rationale for combining biotherapy in the treatment of advanced colon cancer. 1925 92

OverviewPrognostic or Predictive Factors K-ras and Ligands of EGFRCirculating Tumor CellsArray Signatures as Prognostic/Predictive Markers18q and MSI as Prognostic MarkersUse of Thymidylate Synthase To Assign ChemotherapyAccomplishments (or Lack of Accomplishments) Therapy Incorporation of Targeted Therapies in Colon Cancer TreatmentIncorporation of Targeted Therapies in Pancreatic Cancer TreatmentUGT1A1*28 Polymorphism and Irinotecan ToxicityBasic Science Targeting VEGFIdentification of VEGF-Independent PathwaysTargeting EGFRTargeting Other PathwaysFuture Directions Comments on ResearchFuture Challenges.
 ...
PMID:Accomplishments in 2007 in biologic markers for gastrointestinal cancers. 1935 70

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and one of the few malignancies with an increasing incidence in the USA. While the relationship between HCC and its inciting risk factors (e.g., hepatitis B, hepatitis C and alcohol liver disease) is well defined, driving genetic alterations are still yet to be identified. Clinically, HCC tends to be hypervascular and, for that reason, transarterial chemoembolization has proven to be effective in managing many patients with localized disease. More recently, angiogenesis has been targeted effectively with pharmacologic strategies, including monoclonal antibodies against VEGF and the VEGF receptor, as well as small-molecule kinase inhibitors of the VEGF receptor. Targeting angiogenesis with these approaches has been validated in several different solid tumors since the initial approval of bevacizumab for advanced colon cancer in 2004. In HCC, only sorafenib has been shown to extend survival in patients with advanced HCC and has opened the door for other anti-angiogenic strategies. Here, we will review the data supporting the targeting of the VEGF axis in HCC and the preclinical and early clinical development of bevacizumab.
 ...
PMID:Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. 1937 3

Angiogenesis--one of the hallmarks of cancer--has emerged as a valid therapeutic target in oncology. The VEGF system represents a key mediator of tumor-initiated angiogenesis and the first target of antiangiogenesis agents introduced in clinical practice. Although anti-VEGF therapies have clearly demonstrated antitumor efficacy in various malignancies, especially when combined with conventional cytotoxic chemotherapy, their mechanism of action is not fully understood. This Review will discuss the rationale for using antiangiogenic compounds and will focus on large molecules, such as antibodies, that target the VEGF system. Clinical data on bevacizumab is discussed in detail. Predictive markers for anti-VEGF agents have not yet been identified and questions regarding the usefulness of bevacizumab in the adjuvant setting as well as its continued use beyond progression remain unanswered, in spite of negative data on bevacizumab in treating patients with adjuvant colon cancer. Nonetheless, anti-VEGF therapy has enhanced the arsenal of anticancer therapies and has provided new insights into the biology of malignancy.
 ...
PMID:Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. 1963 28

Tumor-associated macrophages are known to influence cancer progression by modulation of immune function, angiogenesis, and cell metastasis, however, little is known about the chemokine signaling networks that regulate this process. Utilizing CT26 colon cancer cells and RAW 264.7 macrophages as a model cellular system, we demonstrate that treatment of CT26 cells with RAW 264.7 conditioned medium induces cell migration, invasion and metastasis. Inflammatory gene microarray analysis indicated CT26-stimulated RAW 264.7 macrophages upregulate SDF-1alpha and VEGF, and that these cytokines contribute to CT26 migration in vitro. RAW 264.7 macrophages also showed a robust chemotactic response towards CT26-derived chemokines. In particular, microarray analysis and functional testing revealed CSF-1 as the major chemoattractant for RAW 264.7 macrophages. Interestingly, in the chick CAM model of cancer progression, RAW 264.7 macrophages localized specifically to the tumor periphery where they were found to increase CT26 tumor growth, microvascular density, vascular disruption, and lung metastasis, suggesting these cells home to actively invading areas of the tumor, but not the hypoxic core of the tumor mass. In support of these findings, hypoxic conditions down regulated CSF-1 production in several tumor cell lines and decreased RAW 264.7 macrophage migration in vitro. Together our findings suggest a model where normoxic tumor cells release CSF-1 to recruit macrophages to the tumor periphery where they secrete motility and angiogenic factors that facilitate tumor cell invasion and metastasis.
 ...
PMID:Chemoattractant signaling between tumor cells and macrophages regulates cancer cell migration, metastasis and neovascularization. 1969 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>