Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Possible pathways of intracellular phosphorylation of 5-fluorouracil (5-FU) in human cancer cells were investigated in vitro and in vivo. We used two inhibitors which regulate the anabolism of 5-FU for the purpose of elucidation of its pathways; one is oxonic acid (Oxo), an inhibitor of orotate phosphoribosyltransferase (OPRTase), catalizing a formation of FUMP from 5-FU, and another is 2, 6-dihydroxypyridine (DP), an inhibitor of uracil ribosyltransferase which catalizes a conversion of 5-FU to 5-fluorouridine. Although the pathway of 5-FU phosphorylation in murine tumor cells was varied, about 80% of human cancer cells tested were found to utilize the first pathway in which 5-FU was converted to FUMP by OPRTase. Thus, the phosphorylation of 5-FU via the first pathway was markedly inhibited by Oxo in 4 strains of 5 gastric cancer cells, 7 of 8 colorectal cancer cells and 3 of 4 lung cancer cells. In xenografts of human gastric and colorectal adenocarcinoma in which 5-FU phosphorylation is regulated by Oxo in vitro, the production of 5-fluoronucleotides and its incorporation into RNA after iv administration of 5-FU significantly decreased by co-administration of Oxo, suggesting that the nature of an anabolic pathway of 5-FU in the tumor cells in vitro reflects in vivo behavior. We also confirmed that the phosphoribosylpyrophosphate level in tumor cells was importantly related to determination of the metabolic pathway of 5-FU. These results would suggest that possible modulation of 5-FU lies on the augmentation of 5-FU efficacy.
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PMID:[Estimation of pathways of 5-fluorouracil anabolism in human cancer cells in vitro and in vivo]. 864 24

A human stomach cancer cell line with acquired resistance to 5-fluorouracil (5-FU), NUGC-3/5FU/ L, has been found to possess reduced ability to convert 5-FU into active metabolites. We attempted in vitro gene therapy for this 5-FU-resistant cell line. NUGC-3 and NUGC-3/5FU/L cells were infected with recombinant adenovirus (Ad) containing Escherichia coli uracil phosphoribosyltransferase (UPRT) gene driven by CAG promoter (CA), AdCA-UPRT, and changes in their 5-FU metabolism and sensitivity were investigated. Activities of orotate phosphoribosyltransferase increased from 10.2 and 1.56 (nmol/mg protein/30 min) in the uninfected cells of NUGC-3 and NUGC-3/5FU/L to 216 and 237, respectively, after the transfection of UPRT gene. The 5-FU nucleotide level in the acid-insoluble fraction increased from 7.32 to 15.9 (pmol/mg protein) in NUGC-3 cells on infection with AdCA-UPRT, and in NUGC-3/5FU/L cells it increased from 1.91 to 21.4. The 50% growth-inhibition concentration (IC50) was 12.7 micromol/liter for NUGC-3 and much higher than 100 micromol/liter for NUGC-3/5FU/L, indicating over 8-fold resistance. NUGC-3/ SFU/L transfected with the UPRT gene showed very high sensitivity to 5-FU with an IC50 of 3.2 micromol/liter. The high resistance in this metabolic activation-deficient cell line was thus completely reversed by transduction of an exogenous gene coding for a 5-FU-anabolizing enzyme.
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PMID:Circumvention of 5-fluorouracil resistance in human stomach cancer cells by uracil phosphoribosyltransferase gene transduction. 1035 51

A new class of 5-halogenated pyrimidine analogs substituted at the 6-position was evaluated as competitive inhibitors of thymidine phosphorylase (TPase). The most potent member of the series was 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidine dio ne hydrochloride (TPI), which has an apparent K(i) value of 1.7 x 10(-8) M. TPI selectively inhibited the activity of TPase, but not that of uridine phosphorylase, thymidine kinase, orotate phosphoribosyltransferase, or dihydropyrimidine dehydrogenase. In vitro inhibition studies of TPI using a thymidine analogue, 5-trifluoromethyl-2'-deoxyuridine (F(3)dThd), as the substrate demonstrated that F(3)dThd phosphorolytic activity was inhibited markedly by TPI (1 x 10(-6) M) in extracts from the liver, small intestine, and tumors of humans, from the liver and small intestine of cynomolgus monkeys, and from the liver of rodents, but not from the liver or small intestine of dogs or the small intestine of rodents, suggesting that the distribution of TPase differs between humans and animal species, and that TPI could contribute to the modulation of TPase in humans. When F(3)dThd or 5-iodo-2'-deoxyuridine (IdUrd) was coadministered to mice with TPI at a molar ratio of 1:1, the blood levels of F(3)dThd (or IdUrd) were about 2-fold higher than when F(3)dThd (or IdUrd) was administered alone. In monkeys, the maximum concentration (C(max)) and the area under the concentration-time curve (AUC) after oral F(3)dThd alone were 0.23 microg/mL and 0.28 microg. hr/mL, respectively, but markedly increased to 15.18 microg/mL (approximately 70-fold) and 28.47 microg. hr/mL (approximately 100-fold), respectively, when combined with equimolar TPI. Combined oral administration of TPI significantly potentiated the antitumor activity of F(3)dThd on AZ-521 human stomach cancer xenografts in nude mice. In conclusion, TPI may contribute not only to inhibition of TPase-mediated biological functions but also to potentiation of the biological activity of various 2'-deoxyuridine and thymidine derivatives by combining with them.
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PMID:Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. 1073 23

Two 5-fluorouracil (5-FU)-resistant cell lines from a Korean gastric cancer cell line were established by incubation of the cells with increasing concentration of 5-FU, and the resultant cell lines showed an over 800-fold increased resistance to 5-FU. To identify the mechanism of 5-FU resistance, the expressions of genes involved in 5-FU metabolism were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Expressions of orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and uridine phosphorylase (UP) were significantly downregulated in these cell lines, resulting in low incorporation of 5-FU into nucleic acids. In contrast, an increased expression of thymidine kinase (TK) was observed in 5-FU-resistant cells. These results strongly indicate that blocking of 5-FU incorporation into nucleic acids and TK overexpression may play a major role in 5-FU resistance in these cells. Interestingly, these cell lines showed cross-resistance to paclitaxel, cisplatin, and doxorubicin, suggesting that other factors such as HSP27 and Mn-SOD could be also involved in the mechanism of multidrug resistance in these cell lines.
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PMID:Establishment and characterization of 5-fluorouracil-resistant gastric cancer cells. 1097 11

A number of enzymes have been shown to be involved in the process of activation and/or degradation of 5-fluorouracil, and they are potential candidates for predicting factors of chemosensitivity to 5-fluorouracil. Among them, orotate phosphoribosyltransferase (OPRT EC 2.4.2.10) is a key enzyme related to the first-step activation process of 5-fluorouracil and therefore it has been shown to be an important enzyme for the prediction of sensitivity to 5-fluorouracil and its related derivatives. We developed a new enzyme-linked immunosorbent assay (ELISA) system to accurately assess intratumoral activity of orotate phosphoribosyltransferase. A new sandwich ELISA system was established using anti-OPRT polyclonal antibodies obtained from the rabbit immunized with the recombinant human peptides of the OPRT molecule. OPRT levels were measured in 8 human cancer xenografts transplanted in nude mice and 58 gastric cancer tissues using both a newly established ELISA and a conventional enzyme assay using radiolabeled 5-fluorouracil as a substrate. OPRT levels in 8 human cancer xenografts measured by this ELISA were significantly correlated with the OPRT enzyme activities (r2=0.782). Furthermore, OPRT activities measured in 58 gastric cancer tissues by enzyme assay were significantly correlated with those measured by the newly-established ELISA (r2=0.664). The ELISA system developed for the measurement of OPRT required a minimal amount of carcinoma tissue samples, which could be an easy-of-use assay system to predict sensitivity to 5-fluorouracil in gastric carcinoma. These results suggest that this newly-developed sandwich ELISA system for the quantification of OPRT is technically simple, feasible, and may be a useful tool to predict sensitivity to fluoropyrimidine-based anticancer chemotherapy in patients with gastric carcinoma and other cancers.
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PMID:[Establishment of enzyme-linked immunosorbent assay for quantification of orotate phosphoribosyltransferase in gastric carcinoma]. 1604 65

A number of enzymes have been shown to be involved in the process of activation and/or degradation of 5-fluorouracil (5-FU), and are potential candidates for predicting chemosensitivity to 5-FU. Among these, orotate phosphoribosyltransferase (OPRT EC 2.4.2.10) is a key enzyme related to the first-step activation process of 5-FU and has been shown to be an important enzyme that helps to predict sensitivity to 5-FU and its related derivatives. We developed a new enzyme-linked immunosorbent assay (ELISA) to accurately assess intratumoral activity of OPRT. A new sandwich ELISA was established using anti-OPRT polyclonal antibodies obtained from the rabbit immunized with the recombinant human peptides of the OPRT molecule. OPRT levels were measured in eight human cancer xenografts and in 75 gastric cancer tissues using both a newly established ELISA and a conventional enzyme assay, using radiolabeled 5-FU as a substrate. There was a significant correlation between OPRT levels measured by this ELISA and OPRT enzyme activity the in eight human cancer xenografts (r2 = 0.782) and gastric carcinoma tissue (r2 = 0.617). The ELISA system for OPRT requires a minimal amount of carcinoma tissue, making it an easy-to-use assay system to predict sensitivity to 5-FU and its derivatives in gastric carcinoma. There was a significant correlation between tumor growth inhibition rates against the oral administration of oral-uracil/tegafur (UFT) and OPRT enzyme activity in the human cancer xenografts (r2 = 0.574). These results suggest that this newly developed sandwich ELISA system for the quantification of OPRT levels is technically simple, feasible and a useful tool to predict sensitivity to fluoropyrimidine-based anticancer chemotherapy in patients with gastric carcinoma and other cancers.
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PMID:Orotate phosphoribosyltransferase levels measured by a newly established enzyme-linked immunosorbent assay in gastric carcinoma. 1673 27

We evaluated the expression of 5-FU pathway genes in prechemotherapeutic fresh frozen samples obtained from primary tumors to predict response and survival of 59 metastatic gastric cancer patients treated with S-1 monotherapy as first line treatment. Five 5-FU pathway genes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP) and uridine phosphorylase (UP), were analyzed by the quantitative real-time reverse transcriptional PCR method. Median values of each gene were selected for cut-off values separating high and low gene expressions. In univariate analyses, low TS, high OPRT and low TP were significantly associated with a tumor shrinkage and a long survival, whereas DPD and UP gene expressions did not correlate with response and survival. Multivariate analyses revealed that independent variables were OPRT and TS for response and TS and TP for survival. When OPRT and TS were combined, a significantly increased accuracy rate of 91.5% was seen for response. Similarly, an increased hazard ratio of 10.29 was observed for survival in patients possessing low TS and low TP, compared with those with high TS or high TP. The simple combinations of 2 genes, OPRT and TS for response and TS and TP for survival, may allow identification of gastric cancer patients who will benefit from S-1 chemotherapy.
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PMID:Simple combinations of 5-FU pathway genes predict the outcome of metastatic gastric cancer patients treated by S-1. 1673 97

Fluoropyrimidines are widely used in chemotherapy regimens for metastatic gastric cancer. Interindividual variation in the enzyme activity of the 5-fluorouracil (FU) metabolic pathway can affect the extent of 5-FU metabolism and affect the efficacy of 5-FU based chemotherapy. In this review, the role of the genetic factors affecting the therapeutic efficacy of fluoropyrimidines is discussed, with a special emphasis on enzymes involved in the 5-FU metabolic pathway. The gene expressions of thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase are discussed in relation to the efficacy of fluoropyrimidine treatment for metastatic gastric cancer. These candidate genes, along with others yet to be identified, could allow accurate prediction of the clinical outcome in patients receiving fluoropyrimidine-based chemotherapy in the future. Well-designed and large prospective studies, which include relevant pharmacogenetic parameters, are needed to confirm the values required to predict clinical outcome.
Gastric Cancer 2006
PMID:Prediction of clinical outcome of fluoropyrimidine-based chemotherapy for gastric cancer patients, in terms of the 5-fluorouracil metabolic pathway. 1695 32

Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), and orotate phosphoribosyltransferase (OPRT) have been reported to be predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy. mRNA expression of TS, DPD, TP, and OPRT were quantified by reverse-transcriptase polymerase chain reaction after harvesting cancer cells from 93 paraffin-embedded specimens of gastric cancer through laser capture microdissection. In vitro chemosensitivity testing by histoculture drug response assay was performed with surgically resected primary lesions of the same 93 patients. No significant correlation was observed between the mRNA expression and location of the tumor, histopathologic type, clinical stage, and other clinicopathologic variables, with the exception that OPRT mRNA had a weak correlation with drug sensitivity against 5FU (R=0.219, p=0.0343). OPRT was considered to have a major impact on drug sensitivity, although not sufficiently so to enable prediction of 5FU sensitivity solely based on the mRNA expression of this enzyme.
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PMID:Gene expression of 5-fluorouracil metabolic enzymes in primary gastric cancer: correlation with drug sensitivity against 5-fluorouracil. 1730 23

To evaluate the protein expression level in formalin-fixed cancer tissue specimens, the authors devised quantitative double-fluorescence immunohistochemistry (qDFIHC). Using this method, the 17 gastric cancer biopsy specimens, before undergoing S-1 based neoadjuvant chemotherapy, were assessed in order to determine the expression levels of the thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) which determines S-1 efficacy. The ratios of OPRT/TS, OPRT/DPD and OPRT/(DPD+TS) which have been proposed to show a good correlation with S-1 efficacy, were calculated and compared with the clinical response. A significant difference was thus observed in OPRT/TS (P=0.0049), OPRT/DPD (P=0.0067) and OPRT/(DPD+TS) (P=0.0013) between the responder and the non-responder groups. Therefore, the ratios assessed by qDFIHC may be a potentially effective predictor of the S-1 efficacy. Furthermore, qDFIHC may also be a useful method for assessing various protein levels in cancer tissues.
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PMID:Quantitative double-fluorescence immunohistochemistry (qDFIHC), a novel technology to assess protein expression: a pilot study analyzing 5-FU sensitive markers thymidylate synthase, dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferases in gastric cancer tissue specimens. 1789 12


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