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)

In spite of recent advances in the treatment of colon cancer, multiple liver metastases of colon cancer are still difficult to treat. Some chemotherapeutic regimens have been reported to be efficient, but there is a high risk of side effects associated with these. Here, we show that isoleucine, an essential amino acid, prevents liver metastases in a mouse colon cancer metastatic model. Because isoleucine is a strong inducer of beta-defensin, we first hypothesized that it prevented liver metastases via the accumulation of dendritic cells or memory T cells through up-regulation of beta-defensin. However, neither beta-defensin nor immunologic responses were induced by isoleucine in both mouse livers and spleens. Furthermore, isoleucine prevented liver metastasis in nude mice, which lack T cells and natural killer T cells. Finally, we discovered a novel mechanism of isoleucine: down-regulation of angiogenesis via inhibition of vascular endothelial growth factor, partially through the mammalian target of the rapamycin pathway, independent of hypoxia-inducible factor 1-alpha. Importantly, isoleucine is safe for administration to humans because it does not affect cell viability. Isoleucine could be a novel prophylactic drug for the prevention of liver metastases of colon cancer.
 ...
PMID:Isoleucine, an essential amino acid, prevents liver metastases of colon cancer by antiangiogenesis. 1740 34

In vitro and in vivo studies have shown that 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits angiogenesis in cancer. We now examined whether the antiangiogenic effects of 1,25(OH)(2)D(3) are mediated by the hypoxia-inducible factor (HIF)-1 pathway. Our results showed that 1,25(OH)(2)D(3) reduces the protein expression of both the regulated HIF-1alpha subunit and the vascular endothelial growth factor (VEGF) in various human cancer cells. 1,25(OH)(2)D(3) also inhibited HIF-1 transcriptional activity (measured by reporter gene assay) as well as HIF-1 target genes, including VEGF, ET-1, and Glut-1. We also showed that 1,25(OH)(2)D(3) inhibits cell proliferation under hypoxia. Using HIF-1alpha knockout colon cancer cells, we show that the inhibition of the hypoxia-induced VEGF by 1,25(OH)(2)D(3) is mediated through a HIF-dependent pathway. Because HIF-1 is a major positive contributor in human tumorigenesis and angiogenesis, we believe that its inhibition by 1,25(OH)(2)D(3) strengthens the rationale to use vitamin D and its low-calcemic analogues in cancer chemoprevention and therapy.
 ...
PMID:1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. 1743 Nov 22

Frequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case-control studies. Coffee is a leading source of methylxanthines, such as caffeine. The induction of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) is an essential feature of tumor angiogenesis, and the hypoxia-inducible factor-1 (HIF-1) transcription factor is known to be a key regulator of this process. In this study, we investigated the effects of caffeine on HIF-1 protein accumulation and on VEGF and IL-8 expression in the human colon cancer cell line HT29 under hypoxic conditions. Our results show that caffeine significantly inhibits adenosine-induced HIF-1alpha protein accumulation in cancer cells. We show that HIF-1alpha and VEGF are increased through A3 adenosine receptor stimulation, whereas the effects on IL-8 are mediated via the A2B subtype. Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression. The mechanism of caffeine seems to involve the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and Akt, leading to a marked decrease in adenosine-induced HIF-1alpha accumulation, VEGF transcriptional activation, and VEGF and IL-8 protein accumulation. From a functional perspective, we observe that caffeine also significantly inhibits the A3 receptor-stimulated cell migration of colon cancer cells. Conditioned media prepared from colon cells treated with an adenosine analog increased human umbilical vein endothelial cell migration. These data provide evidence that adenosine could modulate the migration of colon cancer cells by an HIF-1alpha/VEGF/IL-8-dependent mechanism and that caffeine has the potential to inhibit colon cancer cell growth.
 ...
PMID:Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. 1748 4

To assess whether preoperative chemo-radiotherapy enhances the expression of vascular endothelial growth factor (VEGF) in patients with colorectal cancer, we investigated in vivo and in vitro the interactions between chemo-radiotherapy and the expression of VEGF, and their possible impact on distant metastasis. Cellular cytotoxicity in the colon cancer cell lines, LoVo, SW480 and Caco2, was determined using a WST-8 colorimetric assay after cells were exposed to 5-fluorouracil combined with radiation. In addition, the VEGF levels in cultured cells were measured by ELISA. Preoperative serum samples and tumor specimens were prospectively collected from 32 rectal cancer patients who received preoperative chemo-radiotherapy. Both local and circulating VEGF expression levels were measured perioperatively by ELISA, and assessed in relation to the clinicopathological findings. Perioperative circulating VEGF levels from irradiated patients were also compared with a non-irradiated control group. There were significant increases in local VEGF levels, both in vivo and in vitro, after chemo-radiotherapy, especially in viable cancer cells. The circulating VEGF levels in the irradiated patients were significantly lower after surgery compared with those in the control group. Although preoperative chemo-radiotherapy enhanced tumor-specific VEGF expression, especially in individual cancer cells both in vitro and in vivo, it did not necessarily enhance systemic VEGF expression, possibly because of tumor volume reduction induced by the chemo-radiotherapy.
 ...
PMID:Does preoperative chemo-radiotherapy enhance the expression of vascular endothelial growth factor in patients with rectal cancer? 1761 58

Bevacizumab, a recombinant humanised monoclonal antibody against vascular endothelial growth factor, is approved in Europe as first-line therapy for metastatic breast cancer (mBC) and metastatic carcinoma of the colon or rectum (mCRC); the European Medicines Agency gave a positive opinion recommending its use in non-small-cell lung cancer (NSCLC) and is also considering other indications. In the US, it is licensed for use for mCRC and NSCLC, with its use as first-line treatment in mBC under review by the US FDA. In the pivotal E2100 trial in >700 previously untreated patients with locally recurrent or mBC, recipients of bevacizumab plus paclitaxel had a statistically and clinically significant increase in progression-free survival versus paclitaxel recipients (13.3 vs 6.7 months; hazard ratio 0.48; p < 0.001) [primary endpoint]. There was also a >2-fold higher objective response rate in the bevacizumab plus paclitaxel arm than in the paclitaxel arm; the between-group difference in median overall survival did not reach statistical significance (25.7 vs 23.8 months). Bevacizumab had an acceptable tolerability profile in these patients, with the majority of adverse events being generally mild to moderate in severity. There are targeted adverse events, including gastrointestinal perforations, wound healing complications and haemorrhage, which although they occur infrequently (incidence <=2%), are potentially life-threatening and may cause morbidity.
 ...
PMID:Bevacizumab: in first-line treatment of metastatic breast cancer. 1768 75

For nearly two decades, adjuvant chemotherapy has been the standard of care in patients with early-stage colon cancer at high risk of recurrence. Until now, treatment has been based on the use of cytotoxic drugs that have well-demonstrated efficacy in advanced colorectal cancer. Most recently, targeted biological agents [i.e., antibodies against the epidermal growth factor receptor and vascular endothelial growth factor] have become essential components of the palliative medical treatment of colorectal cancer. Proof of efficacy of these agents in advanced disease has led to the initiation of several trials testing epidermal growth factor receptor and vascular endothelial growth factor antibodies in the adjuvant setting. Although definitive results of ongoing adjuvant studies will not be available for 2 to 3 years, some oncologists might already inappropriately consider the use of these targeted agents as a component of adjuvant therapy in selected patients. Whether the results obtained in advanced colorectal cancer can be readily translated into a projected efficacy in early-stage colon cancer, however, is unclear. In addition, the long-term safety of biological agents in potentially surgically cured patients has not yet been established. This review discusses the potential caveats and concerns associated with the uncritical use of targeted agents as adjuvant therapy before their safety and efficacy in this setting has been indisputably established in definitive phase III trials.
 ...
PMID:Biological therapy and other novel therapies in early-stage disease: are they appropriate? 1800 99

The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-alpha) and vascular endothelial growth factor (VEGF) but were negative for EGFR, human epidermal growth factor receptor 2 (HER2), and VEGFR. Double immunofluorescence staining revealed that tumor-associated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR), and phosphorylated VEGFR (pVEGFR). Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase) or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01); this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001). AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, and increased the level of apoptosis in both tumor-associated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer.
 ...
PMID:Inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation on tumor-associated endothelial cells leads to treatment of orthotopic human colon cancer in nude mice. 1808 14

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.
 ...
PMID:Differential involvement of vascular endothelial growth factor in the survival of hypoxic colon cancer cells. 1817 21

We assessed the antitumor efficacy of KRN951, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptors, using a rat colon cancer RCN-9 syngeneic model in which the tumor cells are transplanted into the peritoneal cavity of F344 rats. KRN951 treatments that commenced 4 days after tumor transplantation (day 4) significantly inhibited tumor-induced angiogenesis, the formation of tumor nodules in the mesenteric windows, and the accumulation of malignant ascites. Moreover, KRN951 treatments initiated on day 14, by which time angiogenesis and malignant ascites have already been well established, resulted in the regression of newly formed tumor vasculatures with aberrant structures and also in the apparent loss of malignant ascites by the end of the study period. Quantitative analysis of the vessel architecture on mesenteric windows revealed that KRN951 not only regressed, but also normalized the tumor-induced neovasculature. Continuous daily treatments with KRN951 significantly prolonged the survival of rats bearing both early stage and more advanced-stage tumors, compared with the vehicle-treated animals. The results of our current study thus show that KRN951 inhibits colon carcinoma progression in the peritoneal cavity by blocking tumor angiogenesis, ascites formation, and tumor spread, thereby prolonging survival. Moreover, these studies clearly demonstrate the therapeutic effects of KRN951 against established tumors in the peritoneal cavity, including the regression and normalization of the tumor neovasculature. Our findings therefore suggest that KRN951 has significant potential as a future therapeutic agent in the treatment of peritoneal cancers with ascites.
 ...
PMID:Anti-tumor activity and tumor vessel normalization by the vascular endothelial growth factor receptor tyrosine kinase inhibitor KRN951 in a rat peritoneal disseminated tumor model. 1820 Dec 72

The design of targeted therapy, particularly patient-specific targeted therapy, requires knowledge of the presence and intratumoral distribution of tyrosine kinase receptors. To determine whether the expression of such receptors is constant or varies between and within individual colon cancer neoplasms, we examined the pattern of expression of the ligands, epidermal growth factor, vascular endothelial growth factor, and platelet-derived growth factor-B as well as their respective receptors in human colon cancer surgical specimens and orthotopic human colon cancers growing in the cecal wall of nude mice. The expression of the epidermal growth factor receptor and the vascular endothelial growth factor receptor on tumor cells and stromal cells, including tumor-associated endothelial cells, was heterogeneous in surgical specimens and orthotopic tumors. In some tumors, the receptor was expressed on both tumor cells and stromal cells, and in other tumors the receptor was expressed only on tumor cells or only on stromal cells. In contrast, the platelet-derived growth factor receptor was expressed only on stromal cells in both surgical specimens and orthotopic tumors. Examination of receptor expression in both individual surgical specimens and orthotopic tumors revealed that the platelet-derived growth factor receptor was expressed only on stromal cells and that the patterns of epidermal growth factor receptor and vascular endothelial growth factor receptor 2 expression differed between tumor cells. This heterogeneity in receptor expression among different tumor cells suggests that targeting a single tyrosine kinase may not yield eradication of the disease.
 ...
PMID:Intratumoral heterogeneity for expression of tyrosine kinase growth factor receptors in human colon cancer surgical specimens and orthotopic tumors. 1820 97


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