Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Few studies have investigated the biological factors associated with sensitivity to bolus infusions of 5-fluorouracil (5FU), including sequential methotrexate (MTX)/5FU therapy. We investigated the relationship between the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), E2F-1, Bcl-2, Bak, and Bcl-X, and the chemotherapeutic effects of sequential MTX/5FU. We studied 38 patients with unresectable or recurrent gastric cancer, treated weekly with sequential MTX/5FU (MTX 100 mg/m2, 5FU 600 mg/m2, by bolus infusions, with a three-hour interval). Expression of the above proteins was examined in initial biopsy samples with immunohistochemical methods. Immunohistochemical reactivity was defined as positive when over 25% of cancer cells showed strong staining in the cytoplasm for TS, TP, DPD, Bak, Bcl-2, and Bcl-X, and in the nucleus for E2F-1. The overall response rate was 28% in the 29 patients who had measurable lesions. Bak-negative patients showed a higher response rate than Bak-positive patients (39% versus 9%, respectively; p=0.1096), although expression of the other proteins was not associated with chemosensitivity. The median survival time (MST) of all patients was 256 days. Bak-negative patients survived significantly longer than Bak-positive patients (MST, 302 days versus 134 days, respectively; p=0.0044). Bcl-X-negative patients survived significantly longer than Bcl-X-positive patients (MST, 302 days versus 215 days, respectively; p=0.0080). Furthermore, patients negative for both Bak and Bcl-X had significantly better prognoses than other patients (MST, 373 days; p<0.0001). Within the limits of the small patient population, multivariate analysis using the Cox proportional hazards model showed that Bak, Bcl-X, and histological type were independent variables predicting survival (p=0.0008, 0.0081, and 0.0082, respectively). Although previously described predictive markers for protracted infusion of 5FU, including TS, TP, and DPD, might not be associated with clinical outcome in patients treated with sequential MTX/5FU, Bak may be a useful marker for chemoresponse and survival. Furthermore, both Bcl-X expression and the coupled expression of Bak and Bcl-X, as well as histological type, may be useful predictive markers for survival.
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PMID:Expression of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, E2F-1, Bak, Bcl-X, and Bcl-2, and clinical outcomes for gastric cancer patients treated with bolus 5-fluorouracil. 1465 96

Regenerating gene family, member 4 (Reg IV), a secreted protein, is overexpressed in several cancers, including gastric cancer (GC). In the present study, we measured Reg IV levels in sera from patients with GC by enzyme-linked immunosorbent assay. We also examined the effect of forced Reg IV expression on the apoptotic susceptibility to 5-fluorouracil (5-FU). Forced expression of Reg IV inhibited 5-FU-induced apoptosis. Induction of Bcl-2 and dihydropyrimidine dehydrogenase was involved in inhibition of apoptosis. Among 36 GC patients treated with a combination chemotherapy of low-dose 5-FU and cisplatin, all 14 Reg IV-positive patients showed no change or disease progression. The serum Reg IV concentration was similar between healthy individuals (mean+/-s.e., 0.52+/-0.05 ng/ml) and patients with chronic-active gastritis (0.36+/-0.09 ng/ml). However, the serum Reg IV concentration in presurgical GC patients was significantly elevated (1.96+/-0.17 ng/ml), even at stage I. The diagnostic sensitivity of serum Reg IV (36.1%) was superior to that of serum carcinoembryonic antigen (11.5%) or carbohydrate antigen 19-9 (13.1%). These results indicate that expression of Reg IV is a marker for prediction of resistance to 5-FU-based chemotherapy in patients with GC. Serum Reg IV represents a novel biomarker for GC.
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PMID:Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy. 1723 19

To elucidate the mechanism of resistance to 5-fluorouracil (5-FU) in human gastric cancer cells, we established a cell line MKN45/F2R, which acquired 5-FU resistance as a result of continuous exposure to increasing dosages of 5-FU over a year. The cell line showed 157-fold elevated 5-FU resistance compared to the MKN45 human gastric cancer parental cell line. Furthermore, the cells acquired crossresistance to paclitaxel and docetaxel. To identify the mechanism of 5-FU resistance, the expressions of 5-FU metabolic enzymes were examined. Although protein expression and activity of thymidylate synthase and dihydropyrimidine dehydrogenase did not change, orotate phosphoribosyl-transferase (OPRT) protein expression and activity significantly decreased in the 5-FU resistant MKN45/F2R cells. Interestingly, expression of proteins related to taxane resistance including P-glycoprotein, class III beta-tubulin and Bcl-2 increased in MKN45/F2R cells. OPRT-knockout MKN45 parent cells using small interfering RNA demonstrated 15.8-fold increased resistance to 5-FU compared to the control cells. However, resistance to paclitaxel and docetaxel was not observed. These results strongly indicate that decreased activity of OPRT plays an important role in the acquired resistance of gastric cancer cells towards 5-FU; however, it does not play a direct role in paclitaxel and docetaxel resistance. Further studies are now underway to identify genes related to crossresistance to these chemotherapeutic agents.
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PMID:Decreased orotate phosphoribosyltransferase activity produces 5-fluorouracil resistance in a human gastric cancer cell line. 1902 Jul 40

The aim of the present study was to investigate the role of NK4, an antagonist for hepatocyte growth factor (HGF) and the Met receptor, in regulating the response of cholangiocarcinoma (CCA) cells to 5-fluorouracil (5-FU). We established the CCA cell line, HuCC-T1, to produce abundant NK4 (Hu-NK4). Cell proliferation, cell cycle distribution, apoptosis, 5-FU metabolism and intracellular signaling were examined. There were no significant differences in the mRNA levels of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase between the mock-transfected control Hu-Em cells and Hu-NK4 cells, suggesting that NK4 expression does not alter 5-FU metabolism. Moreover, cell cycle analysis showed that 5-FU treatment caused a decrease in the proportion of cells in the G2/M phase while NK4 gene expression had little effect on the cell cycle distribution. However, 5-FU-induced apoptosis was significantly increased in the Hu-NK4 cells when compared to that in the Hu-Em cells. Further investigation revealed that NK4 gene expression enhanced 5-FU-induced caspase-3 and caspase-9 activation, and that the apoptosis of cells was associated with modulation of expression of the Bcl-2 family members. Furthermore, western blot analysis revealed that both NK4 and 5-FU were inhibitors for HGF-induced phosphorylation of Met, but they may be independent factors. Collectively, these results suggest that following 5-FU treatment in CCA cell lines, NK4 was involved in apoptosis induction through the intrinsic mitochondrial pathway. This indicates that NK4 may be an important mediator of 5-FU-induced cell death. Moreover, downregulation of NK4 in response to 5-FU may represent an intrinsic mechanism of resistance to this anticancer drug.
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PMID:NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway. 2361 66

A 56-year-old man was diagnosed to have a huge gastric cancer extending from the lesser curvature of the stomach to the pancreas with multiple hepatic and peritoneal metastases. Two days after completing chemotherapy with cisplatin plus high dose leucovorin and fluorouracil, drastic necrotising tumour lysis led to gastric perforation and septic shock most likely due to bacterial peritonitis. The image of tumour lysis looked like an emphysematous pancreatitis. Afterwards, immunohistochemical study of the tumour specimen confirmed moderate positivity of dihydropyrimidine dehydrogenase and absence of Bcl-2 expression. The incomplete expression of dihydropyrimidine dehydrogenase and total deficiency of Bcl-2 are considered to be the main underlying causes of such extraordinary chemosensitivity and so severe a tumour lysis phenomenon. Pre-emptive intensive survey of possible biomarkers of chemosensitivity is thus highly recommended upon treating a massive gastric cancer.
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PMID:Chemotherapy-induced necrotising tumour lysis and perforation of a huge gastric cancer simulating emphysematous pancreatitis. 3258 69