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 pyrimidine acyclonucleoside benzyloxybenzyloxybenzylacyclouridine (BBBAU) showed growth inhibitory activity against the human colon cancer HCT-8 cell line with a 50% inhibitory concentration of 55 microM. Unlike its parent compounds, BBBAU was an extremely weak inhibitor of uridine phosphorylase. This acyclonucleoside analogue is an inhibitor of thymidylate synthase (TS) as determined by inhibition of [6-3H]-2'-deoxyuridine incorporation into DNA, inhibition of 3H release from [5-3H]-2'-deoxyuridine, and decrease in both the free and total TS 5'-fluoro-2'-deoxyuridine 5'-monophosphate binding sites. Kinetic analysis revealed that BBBAUMP, the monophosphate analogue of BBBAU, is a competitive inhibitor of purified human recombinant TS with a Ki of 8.0 microM. Nucleoside transport and uptake studies revealed that BBBAU (30 microM) inhibited the initial rate of transport and the total uptake of thymidine (25 microM). In contrast, while BBBAU (30 microM) inhibited the initial rate of transport of 5-fluoro-2'-deoxyuridine (FdUrd, 25 microM), its intracellular accumulation was increased. BBBAU (10 and 50 microM, respectively) potentiated FdUrd growth inhibition of HCT-8 cells and significantly enhanced the cytotoxic effects of FdUrd (0.3 and 1 microM, respectively) against HCT-8 cells using a clonogenic assay system. This combination resulted in additive inhibitory effects on TS activity resulting in greater depletion of dTTP pools. Moreover, the incorporation of radiolabeled FdUrd into the DNA fraction of HCT-8 cells was enhanced. The potential importance of this novel combination for human colon cancer chemotherapy is discussed.
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PMID:Enhancement of 5-fluoro-2'-deoxyuridine antineoplastic activity by 5-benzyloxybenzyloxybenzylacyclouridine in a human colon carcinoma cell line. 153 44

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

Orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), uridine phosphorylase (UP), dihydropyrimidine dehydrogenase (DPD), and thymidylate synthetase (TS) are enzymes which analyze the salvage synthesis within the biosynthesis of the nucleic acid route of colon cancer. These enzymes were measured in carcinoma and normal tissue. OPRT was 0.065 +/- 0.041 nmol/min/mg protein, TP 4.04 +/- 2.81 nmol/min/mg protein, UP 1.79 +/- 1.19 nmol/min/mg protein, DPD 23.8 +/- 12.0 pmol/min/mg protein, and TS 6.1 +/- 4.4 pmol/g tissue in the normal tissue, and OPRT was 0.199 +/- 0.146 nmol/min/mg protein, TP 13.63 +/- 6.04 nmol/min/mg protein, UP 5.84 +/- 2.37 nmol/min/mg protein, DPD 22.0 +/- 13.4 pmol/min/mg protein, TS 16.9 +/- 7.8 pmol/g tissue in the carcinoma. OPRT, TP, and UP in the carcinoma mainly existed about 3.06-3.37 times that in normal tissue and TS at about 2.77 times. No significant difference was seen in DPD. A correlation was found between OPRT in normal tissue and carcinoma. Biosynthesis of nucleic acid via salvage synthesis is actively stimulated. Enzymatic activity related to uracil was high, and was thought to be closely connected to the growth of the cancer.
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PMID:[Analysis of the salvage synthesis within biosynthesis of nucleic acid route in colon cancer]. 1096 98

The attainment of chemoresistance during tumor metastasis is often experienced. In this study, we evaluated the correlation between sensitivity to 5-fluorouracil (5-FU) and the mRNA expression level of several 5-FU-related metabolic enzymes [thymidylate synthase, dihydropyrimidine dehydrogenase (DPD), thymidylate phosphorylase (TP), orotate phosphoribosyl transferase, and uridine phosphorylase] in primary colorectal cancer and synchronous liver metastases from ten patients to investigate how colorectal cancer acquires 5-FU resistance during liver metastases. A liver metastasis model of xenotransplanted human colon cancer cell line (HCT116) in nude mice and several cell lines from metastatic liver tumors were also established and analyzed. Chemosensitivity and mRNA expression levels were measured by using collagen gel droplet-embedded culture drug sensitivity tests and real-time quantitative reverse transcription-polymerase chain reaction. Metastatic liver tumors were significantly more resistant to 5-FU than primary colorectal cancer (T/C, 88.7% versus 69.7%, p<0.05). DPD and TP mRNA levels were significantly higher in metastatic liver tumors (DPD: 10.36+/-1.81 versus 3.95+/-0.99, p<0.01; and TP: 18.80+/-4.96 versus 7.28+/-1.23, p<0.05) and inversely correlated with 5-FU sensitivity (DPD: R=0.570, p<0.05; TP: R=0.600, p<0.05). In the mouse model, metastatic liver tumors were significantly more resistant to 5-FU than HCT116 (T/C, 92.7%, 96.2% versus 68%, p<0.001). The DPD and TP mRNA levels increased with repeated liver metastases. DPD and TP may affect the acquisition of resistance to 5-FU during liver metastasis of colorectal cancer. This mouse model may be useful for analyzing the mechanisms of how colorectal cancer acquires resistance to 5-FU during liver metastases.
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PMID:Correlation between chemosensitivity and mRNA expression level of 5-fluorouracil-related metabolic enzymes during liver metastasis of colorectal cancer. 1652 74

Thymidine phosphorylase (TP) and uridine phosphorylase (UP) are often upregulated in solid tumors and catalyze the phosphorolysis of natural (deoxy)nucleosides and a wide variety of fluorinated pyrimidine nucleosides. Because the relative contribution of each of the two enzymes to these reactions is still largely unknown, we investigated the substrate specificity of TP and UP in colon cancer cells for the (fluoro)pyrimidine nucleosides thymidine (TdR), uridine (Urd), 5'-deoxy-5-fluorouridine (5'DFUR), and 5FU. Specific inhibitors of TP (TPI) and UP (BAU) were used to determine the contribution of each enzyme in relation to their cytotoxic effect. The high TP expressing Colo320TP1 cells were most sensitive to 5'DFUR and 5FU, with IC50 values of 1.4 and 0.2 microM, respectively, while SW948 and SW1398 were insensitive to 5'DFUR (IC50>150 microM for 5'DFUR). TPI and BAU only moderately affected sensitivity of Colo320, SW948, and SW1398, whereas TPI significantly increased IC(50) for 5'DFUR (50-fold) and 5FU (11-fold) in Colo320TP1 and BAU that in C26A (9-fold for 5'DFUR; p<0.01). In the epithelial skin cell line HaCaT both inhibitors were able to decrease sensitivity to 5'DFUR and 5FU separately. HaCaT might be a model for 5'DFUR toxicity. In the colon cancer cells 5'DFUR degradation varied from 0.4 to 50 nmol 5FU/h/10(6)cells, that of TdR from 0.3 to 103 nmol thymine/h/10(6)cells, that of Urd from 0.8 to 79 nmol uracil/h/10(6)cells, while conversion of 5FU to FUrd was from 0.3 to 46 nmol/h/10(6)cells. SW948 and SW1398 were about equally sensitive to 5'DFUR and 5FU, but SW1398 had higher phosphorylase activity (>65-fold) compared to SW948. In SW948 and HaCaT TPI and BAU inhibited TdR and Urd phosphorolysis (>80%), respectively. Both TP and UP contributed to the phosphorolysis of 5'DFUR and 5FU. In the presence of both inhibitors, still phosphorolysis of 5FU (>40%) was detected in the tumor and HaCaT cell lines, and remarkably, that of all four substrates in SW1398 cells. 5'DFUR phosphorolysis was also measured in situ, where Colo320TP1, SW1398, and HaCaT cells produced significant amounts 5FU from 5'DFUR (>10 nmol/24h/10(6)cells). In Colo320TP1 and in HaCaT cells TPI completely prevented 5FU production, but not in SW1398 cells, where BAU decreased this by 67% (p<0.01). High uracil and dUrd levels were detected in the medium. Uracil accumulation was heavily reduced in the presence of TPI for Colo320TP1 and HaCaT cells, whereas 5FU-induced dUrd production by these cell lines increased (p<0.01). In contrast, for SW1398 cells only BAU was able to reduce uracil levels, and dUrd production remained unchanged. In conclusion, overlapping substrate specificity was found for TP and UP in the cell lines, in which both enzymes were responsible for converting TdR and Urd, and 5'DFUR. 5'DFUR and 5FU were converted to their products in both the colon cancer cells and keratinocytes.
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PMID:Activity and substrate specificity of pyrimidine phosphorylases and their role in fluoropyrimidine sensitivity in colon cancer cell lines. 1709 63

Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is capable of coactivating several nuclear receptors and transcription factors that participate in the regulation of multiple metabolic processes, including gluconeogenesis, mitochondrial biogenesis, and adaptive thermogenesis. Uridine phosphorylase (UPase) catalyzes the reversible conversion of uridine into uracil and contributes to the antineoplastic activity of 5'-deoxy-5-fluorouridine (5'-DFUR) and homeostasis of uridine levels in plasma and tissues. This study demonstrates uridine phosphorylase as a novel target gene of PGC-1alpha, which induces the transcription and enzymatic activity of UPase in various cancer cells and thus augments their susceptibility to 5'-DFUR. PGC-1alpha-induced activation of UPase expression occurs at its transcription level that is mediated by an estrogen-related receptor (ERR) binding site (-1078 to -1070 base pairs) mapped in the promoter region of UPase gene. Our mutational studies using luciferase reporter construct together with electrophoretic mobility shift assays confirm the binding of ERR to PGC-1alpha-responsive element. Moreover, the inhibition of PGC-1alpha/ERRalpha-dependent signaling by 3-[4-(2,4-bis-trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)acrylamide (XCT790) compromises the ability of PGC-1alpha to induce the transcript of UPase, indicating PGC-1alpha-dependent and ERRalpha-mediated up-regulation of UPase. Finally, the overexpression of PGC-1alpha sensitizes breast and colon cancer cells to growth inhibition by 5'-DFUR presumably by inducing apoptosis in tumor cells and XCT790 can inhibit the process. Taken together, our results corroborate the regulatory function of PGC-1alpha in uridine homeostasis and imply its links with the energy metabolism. The mechanistic elucidation of this association between both cellular pathways should advance the clinical use of 5-fluorouracil-based chemotherapy.
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PMID:Peroxisome proliferator-activated receptor gamma coactivator-1alpha enhances antiproliferative activity of 5'-deoxy-5-fluorouridine in cancer cells through induction of uridine phosphorylase. 1960 72

Uridine (Urd) is a promising biochemical modulator to reduce host toxicity caused by 5-fluorouracil (5-FU) without impairing its antitumor activity. Elevated doses of Urd are required to achieve a protective effect against 5-FU toxicity, but exogenous administration of Urd is not well-tolerated. Selective inhibitors of human uridine phosphorylase (hUP) have been proposed as a strategy to increase Urd levels. We describe synthesis and characterization of a new class of ligands that inhibit hUP type 1 (hUP1). The design of ligands was based on a possible SN1 catalytic mechanism and as mimics of the carbocation in the transition state of hUP1. The kinetic and thermodynamic profiles showed that the ligands here presented are the most potent in vitro hUP1 inhibitors developed to date. In addition, a lead compound improved the antiproliferative effects of 5-FU on colon cancer cells, accompanied by a reduction of in vitro 5-FU cytotoxicity in aggressive SW-620 cancer cells.
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PMID:Design of novel potent inhibitors of human uridine phosphorylase-1: synthesis, inhibition studies, thermodynamics, and in vitro influence on 5-fluorouracil cytotoxicity. 2413 20