Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

A hepatocyte-derived cell line designated MLE-15A2 was established from a primary culture of mouse hepatocytes. The MLE-15A2 cells appeared to retain the basic nature of hepatocytes in that they showed morphology of an epithelial cell type and secreted albumin into the culture medium. These cells were grown on collagen-coated plates and could be easily expanded to a large-scale culture. Therefore, MLE-15A2 cells may provide a more useful model for studying liver microenvironments than primary cultures of hepatocytes. We found that conditioned media from MLE-15A2 cells, as well as from primary cultures of hepatocytes, promoted the proliferation of highly liver-colonizing colon 26 NL-17 cells better than the poorly liver-colonizing colon 26 NL-4 cells. Moreover, the conditioned media stimulated the growth of some human colon cancer cell lines. These results indicate that MLE-15A2 cells secrete growth factors that selectively stimulate certain tumor cell types. Hepatocyte-derived growth factors may regulate selective survival and colonization of tumor cells in the process of liver metastasis. The growth-promoting activity was unaffected by dialysis, was stable at 80 degrees C for 30 minutes and was bound to a heparin-Sepharose column. The major activity was eluted from the column with 0.7-0.75 M NaCl, and some minor activities eluted with lower concentrations of NaCl. These results suggest that the active components are heterogeneous heparin-binding proteins with lower affinity to heparin than platelet-derived and fibroblast growth factors.
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PMID:Establishment of a hepatocyte cell line producing growth-promoting factors for liver-colonizing tumor cells. 860 63

Platelet-derived endothelial cell growth factor may play a role in tumor development through its angiogenic action. To clarify the relationship between expression of platelet-derived endothelial cell growth factor and microvessel density in the development of human colon carcinoma, we examined 80 early-stage colon carcinomas using microscopy and immunohistochemistry. Localization of platelet-derived endothelial cell growth factor was assessed by immunocytochemistry, while microvessel count was evaluated by either HE staining or Factor VIII immunostaining. Among the examined carcinomas, 35 were classified as m carcinomas including carcinoma in situ, whereas 45 were sm carcinomas. Fifteen (42.9%) of the 35 m and 30 (66.7%) of the 45 sm carcinomas demonstrated high vascular density, whereas 20 (57.1%) m and 15 (33.3%) sm carcinomas showed moderate or low vascular density. Vascular density was higher in sm carcinomas than in m carcinomas and there was a significant correlation between depth of invasion and vascular density. Of the 45 highly vascularized carcinomas, 44 expressed platelet-derived endothelial cell growth factor. There was a statistically significant correlation between the frequency of platelet-derived endothelial cell growth factor expression and microvessel density (P = 0.012). These data demonstrate that microvessel density may be associated with the depth of cancer invasion and that platelet-derived endothelial cell growth factor may play an important role in the early stage of colon cancer development through angiogenesis.
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PMID:Correlation between expression of platelet-derived endothelial cell growth factor (thymidine phosphorylase) and microvessel density in early-stage human colon carcinomas. 937 8

We have previously shown that platelet-derived endothelial cell growth factor (PD-ECGF) is associated with angiogenesis of human colon cancer; this factor is expressed at high levels in vascular tumors that express low levels of vascular endothelial growth factor (VEGF). In these colon cancers, the major source of PD-ECGF is the infiltrating cells. In this study, we examined the role of PD-ECGF in the angiogenesis of human gastric cancer. Immunostaining for PD-ECGF was done on 93 gastric cancers previously stained for VEGF, basic fibroblast growth factor, and factor VIII-related antigen (specific for endothelial cells). To determine the cell type expressing PD-ECGF, double staining was done using antibodies to both PD-ECGF and CD68 (specific for macrophages). PD-ECGF was expressed more frequently in infiltrating cells (positive CD68 staining; 53.8%) than in tumor epithelium (9.7%; P < 0.0001). Infiltrating cells simultaneously stained positive for both PD-ECGF and CD68. An association between PD-ECGF expression in infiltrating cells, VEGF expression in tumor epithelium, and vessel count was observed in intestinal-type gastric cancer but not in diffuse-type gastric cancer. Vessel count was greater in tumors with high expression of both PD-ECGF and VEGF than in those with high expression of either factor alone (P = 0.002). Multiple angiogenic factors expressed by both tumor cells and infiltrating cells may play a role in the regulation of angiogenesis in intestinal-type gastric cancer.
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PMID:Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer. 951 32

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) and its intermediate metabolite [5'-deoxy-5-fluorouridine (5'-dFUrd)] to 5-fluorouracil in tumors. We have tried to identify the best partners of capecitabine in combination therapy, such as dThdPase up-regulators, which may enhance the efficacy of this compound. Among various cytostatics studied with the WiDr human colon cancer xenograft model, Taxol, Taxotere, and mitomycin C greatly increased levels of human dThdPase in tumors, and cyclophosphamide slightly increased the enzyme level. These cytostatics simultaneously increased the levels of human tumor necrosis factor alpha (TNFalpha), which is an up-regulator of dThdPase. In cultures of the WiDr cells, however, Taxol did not up-regulate TNFalpha to a detectable level and only slightly enhanced levels of dThdPase. These results suggest that Taxol might indirectly elevate TNFalpha in tumor cells, which in turn up-regulated dThdPase in the tumor cells in the WiDr cancer xenograft. In the combination therapy, the efficacy of Taxol and Taxotere with either capecitabine or 5'-dFUrd was more than just additive. In contrast, Taxol and either 5-fluorouracil or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Taxol and Taxotere might enhance the efficacy of capecitabine and 5'-dFUrd, probably by modulating dThdPase activity in tumor tissues.
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PMID:Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. 956 97

Thymidine phosphorylase (dThdPase) is an enzyme that converts 5'-deoxy-5-fluorouridine (5'DFUR) to the toxic substance 5-fluorouracil (5-FU); it is also known to be a platelet-derived endothelial cell growth factor. In order to investigate the feasibility of suicide gene therapy against colorectal cancer by means of the combination of 5'DFUR and the converting enzyme dThdPase, we transfected the dThdPase gene into the human colon cancer cell line SW480 and analyzed the growth pattern as well as the sensitivity to 5-FU or 5'DFUR of the dThdPase-transfected cells. The 50% inhibition (IC50) values of 5-FU against the SW480 parental cells, control vector-transfected cells SW480/V1, and dThdPase-transfected cells SW480/dThdPase were approximately 4.9, 6.3, and 2.9 microM, respectively. The IC50 of SW480/dThdPase was lower than that of SW480 or SW480/V1, although the differences were not statistically significant. The IC50 values of 5'DFUR for SW480, SW480/V1, and SW480/dThdPase were approximately 300, 330, and 3.2 microM, respectively. The sensitivity to 5'DFUR of SW480/dThdPase was increased by about 100-fold compared with that of SW480 or SW480/V1. With only 10% transfection efficacy, a high enough sensitivity to 5'DFUR was obtained to suppress the cell growth, indicating that a strong bystander effect was induced by this system. The in vivo growth of the s.c. transplanted SW480/dThdPase tumor in nude mice was significantly suppressed by i.p. injection of 5'DFUR compared with that in control mice that received phosphate-buffered saline (PBS) treatment. These results suggest that gene therapy using the combination of 5'DFUR and the dThdPase gene may be a useful approach for treatment of colon cancer.
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PMID:Enhancement of the anti-tumor effect of 5'-deoxy-5-fluorouridine by transfection of thymidine phosphorylase gene into human colon cancer cells. 1036 85

Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the oral cytostatic drugs capecitabine (N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine, Xeloda(trade mark)) and its intermediate metabolite doxifluridine [5'-deoxy-5-fluorouridine (5'-dFUrd, Furtulon((R)))] to 5-fluorouracil (5-FUra) in tumors. In a previous study, we found that several cytostatics were able to up-regulate tumor levels of dThdPase in a human colon cancer xenograft model. In the present study, we confirmed that the administration of cytostatics used for breast cancer treatment, such as taxanes and cyclophosphamide (CPA), up-regulated the tumor level of dThdPase in mammary tumor models as well. Because the dThdPase up-regulation was observed even when CPA was given orally, we investigated further the usefulness of combination therapy with the 2 oral drugs, 5'-dFUrd/capecitabine and CPA in mammary tumor models. Daily oral administration of CPA up-regulated human dThdPase levels in the tumor tissue of mice bearing a human mammary tumor xenograft, MX-1, whereas in the small intestine and liver, it did not affect levels of pyrimidine nucleoside phosphorylases (PyNPase) including dThdPase and uridine phosphorylase. The preferential up-regulation of PyNPase activity in the tumor by CPA administration was also confirmed in mice bearing a syngeneic murine mammary adenocarcinoma, A755. In both models, combination therapy of 5'-dFUrd/capecitabine with CPA showed synergistic antitumor activity, without significant potentiation of toxicity. In contrast, treatment with CPA and either 5-FUra or UFT (a mixture of tegafur and uracil) in combination showed only additive activity. Our results suggest that CPA and capecitabine/5'-dFUrd, both available for oral administration, would be good partners, and that clinical trials with this drug combination against breast cancer are warranted.
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PMID:Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5'-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models. 1044 19

Thymidine phosphorylase (TP; also known as platelet-derived endothelial cell growth factor, PD-ECGF) is an angiogenic factor that is chemotactic for endothelial cells and has been found to induce neovascularization in vivo. TP is frequently overexpressed in human solid tumors, where its expression has been correlated with increased tumor microvessel density, invasion, and metastasis, and shorter patient survival. In this report, TP activity in the WiDr colon carcinoma cell line was found to be induced 100-fold by tumor necrosis factor (TNFalpha), a secretory product of activated macrophages that has indirect angiogenic activities. Increased TP activity was accompanied by increased TP mRNA levels and without an increase in mRNA stability. TNFalpha-induced TP mRNA levels were reduced by mithramycin, a DNA-binding transcription inhibitor specific for GC-rich sequences. Transcriptional regulation by TNFalpha was confirmed by transient transfection of WiDr with upstream TP sequences in a luciferase reporter construct. Deletion analysis of the reporter pinpointed two regions of the TP promoter with regulatory elements for both TNFalpha-inducible and basal expression, and they contained, respectively, three and one consensus binding sites for the Sp1-family of transcription factors. One additional region contributed only to basal TP expression, and it contained three Sp1 sites. TNFalpha-induced TP expression decreased when point mutations were made in three of the four Sp1 sites postulated to contribute to both basal and TNFalpha-inducible expression. Electrophoretic mobility shift assays further demonstrated binding of nuclear Sp1 to these three sites. Sp1-binding activity was also increased in cells treated with TNFalpha. These studies establish a role for Sp1 in the regulation of expression of the angiogenic factor TP in colon cancer WiDr cells.
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PMID:The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells. 1246 67

We previously reported that vessel count, vascular endothelial growth factor (VEGF) and platelet derived endothelial cell growth factor (PD-ECGF) expression are associated with metastasis formation in human colon cancer. This study was done to determine a stage of colon cancer progression where induction of these factors occurred (i.e. the angiogenic switch). We examined vessel count, VEGF, and matrix metalloproteinase (MMP)-7 expression in cancer cells and PD-ECGF expression in infiltrating cells in 25 adenomas, 35 mucosal cancers (Tis), 29 submucosal invasive cancers (T1) and 33 muscularis propria invasive cancers (T2) by immunostaining. The intensity of staining of VEGF and MMP-7 was evaluated blindly at the invasive edge and was confirmed by image analysis. Intensity of staining for these factors was graded on a scale of 0 to 3+, with 0 representing no detectable stain and 3+ representing the strongest stain. Intensites of PD-ECGF-positive infiltrating cells were similar on a scale 0 to 3+, as previous studies from our laboratory have demonstrated that PD-ECGF is expressed primarily in tumor infiltrating cells. The vessel density was 12.7+/-2.2 (SE) in adenoma, 11.8+/-1.7 in Tis, 35.0+/-6.5 in T1, and 35.2+/-5.3 in T2. There were significant differences in vessel densities between Tis and T1 (p<0.001). The intensities of VEGF expression were 0.6+/-0.1, 0.9+/-0.2, 1.7+/-0.3, and 1.8+/-0.3 for adenoma, Tis, T1 and T2, respectively, with significant differences between in Tis and T1 (p<0.001). There were also significant differences in the intensities of the expression of MMP-7 and PD-ECGF between Tis and T1. These results suggest that angiogenic switch may occur between Tis and T1, i.e. simultaneous to initiation of invasion, in the early development of colon cancer.
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PMID:The angiogenic switch of human colon cancer occurs simultaneous to initiation of invasion. 1246 36

Platelet derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) catalyzes the phosphorolysis of thymidine (TdR) to thymine and deoxyribose-1-phosphate (dR-1-P) and has a pro-angiogenic effect for which dR-1-P may be responsible. Using a purine nucleoside phosphorylase based assay it was found that TdR incubation did not increase dR-1-P accumulation in colon cancer cell line Colo320 and its PD-ECGF/TP transfected variant Colo320TP1. The assay was linear up to 25,000pmol dR-1-P with complete recovery of dR-1-P from cellular extracts. There was a huge discrepancy between thymine production and the measured dR-1-P level, 0.05% of the expected value for dR-1-P was found, indicating that there was a rapid disappearance of dR-1-P. However, in cellular extracts, TdR incubation increased dR-1-P, measurable by trapping, which was inhibited by a thymidine phosphorylase inhibitor. dR-1-P directly added to cellular extracts disappeared within 5-10min. In conclusion, large amounts of dR-1-P are produced by Colo320TP1 cells, which rapidly disappear thus not resulting in a net accumulation of dR-1-P in these cells.
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PMID:Rapid disappearance of deoxyribose-1-phosphate in platelet derived endothelial cell growth factor/thymidine phosphorylase overexpressing cells. 1256 33

Human thymidine phosphorylase (dThdPase) is an angiogenic factor identical to platelet-derived endothelial cell growth factor (PD-ECGF). Thymidine phosphorylase is also a converting enzyme of the prodrug 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU) in tumors. To assess the role of dThdPase in targeting chemotherapy, we examined the relationship between the expression of dThdPase and the sensitivity of 5'-DFUR in cancer cell lines, and also examined whether transfection of dThdPase cDNA enhanced the drug-sensitivity to 5'-DFUR with or without angiogenesis in breast cancer cells. Thirteen human cancer cell lines consisting of 4 breast cancer, 6 gastric cancer, and 3 colon cancer cell lines were used. Expression of dThdPase was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). In vitro drug-sensitivity was assessed by MTT assay, and anti-tumor effect in vivo was assessed using nude mouse xenografts. Intratumoral microvessel density was evaluated by immunohistochemical staining to factor VIII related antigen. Transfection of dThdPase cDNA was performed using pcDNA3 expression vector encoding its cDNA by the lipofection method. An inverse relationship between the expression of dThdPase and the IC50 values of 5'-DFUR was observed (p=0.1278, rho=-0.440) in the 13 cancer cell lines. Transfection of dThdPase cDNA into MCF-7 breast cancer cells resulted in an approximately 2.6- and 10-fold increase of the expression of dThdPase mRNA and its enzyme activity, respectively, compared to the control vector alone. The sensitivity to 5'-DFUR in the transfected cells was increased approximately 20-fold compared to the parent cells and control vector alone, and the sensitivity to 5-FU was also somewhat increased. In contrast, the sensitivity to ADM, CDDP, and VP-16 was not different between the transfected and control cells. In nude mice xenografts of the transfected cells, treatment with 5'-DFUR had a significant anti-tumor effect compared to those of the untreated transfected cells and control vector alone treated with 5'-DFUR (p<0.01). Intratumoral microvessel density in the transfected cells was not significantly increased with or without treatment with 5'-DFUR compared to control vector alone. The high expression of dThdPase was correlated with an increase in the sensitivity to 5'-DFUR in gastrointestinal and breast cancer cell lines. The introduction of dThdPase cDNA in breast cancer cells enhanced the sensitivity to 5'-DFUR without an increase of tumor angiogenesis, and targeting chemotherapy of dThdPase may be a good tumor-specific and personalized therapy for improving the poor prognosis of cancer patients who show high expressions of dThdPase.
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PMID:Effects of introduction of dThdPase cDNA on sensitivity to 5'-deoxy-5-fluorouridine and tumor angiogenesis. 1263 76


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