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

A 75-year-old female patient with impaired renal function caused by aging was treated with TS 1 for gastric cancer with extensive multiple liver metastases. TS-1 contains CDHP, which inhibits DPD activity and maintains a high blood concentration of 5-FU. Because CDHP is excreted from the kidney, a careful TS-1 administration is necessary for patients with impaired renal function considering an occurrence of severe adverse events. Based on the result previously reported by us about pharmacokinetic study and recommended administration dosage of TS-1 for patients with impaired renal function, we administered 50 mg/day of TS-1 for four weeks followed by two weeks rest per one course for this patient. The patient's creatinine clearance calculated by the Cockcroft-Gault method was 38 ml/min, and we reduced the administration dosage in consideration of her impaired renal function, although normal dosage of TS-1 calculated from body surface area for this patient was 100 mg/day. As this patient underwent TS-1 treatment, sizes of multiple liver metastases and the blood concentration level of CEA were gradually reduced, and the reductive rate of the former was more than 90% and the level of the latter fell to a normal range after 12 courses of TS 1 treatment. Through all the treatment courses, relative drug intensity was 100% and the performance status of this patient was kept 0 without any grade 3 or more adverse events under ambulatory treatment. A successful treatment for this patient might indicate that it was important to consider the appropriate reduction of the dosage of TS-1 administration for elderly patients with gastric cancer, because there is a reverse correlation between aging and renal function. To clarify this problem, a multicenter prospective phase II study about TS-1 reductive administration depending on the renal function for elderly patients with gastric cancer (OGSG0404) is ongoing in our clinical study group (OGSG; Osaka Gastrointestinal Chemotherapy Study Group).
 ...
PMID:[A case of an elderly patient with gastric cancer successfully treated with TS-1 considering impaired renal function caused by aging]. 1721 38

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.
 ...
PMID:Reg IV is a serum biomarker for gastric cancer patients and predicts response to 5-fluorouracil-based chemotherapy. 1723 19

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.
 ...
PMID:Gene expression of 5-fluorouracil metabolic enzymes in primary gastric cancer: correlation with drug sensitivity against 5-fluorouracil. 1730 23

Dihydropyrimidine dehydrogenase (DPD) is the enzyme catalyzing the first step of pyrimidine metabolism. To date, genetic polymorphisms of pyrimidine-synthesizing enzymes have been reported to be associated with the risk of malignant lymphoma or colon cancer. Accordingly, there may be associations between dihydropyrimidine dehydrogenase (DPYD) polymorphism and the risk of malignancies. We conducted a prevalent case-control study to investigate the associations between a functional polymorphism of dihydropyrimidine dehydrogenase, DPYD T85C, and the risk of six malignancies. Controls were 445 Nagoya City inhabitants without a history of malignancy who had participated in a health check-up between August and September 2000. Case subjects were 901 patients with malignancies (99 esophageal, 131 gastric, 143 colon, 179 lung, 243 breast, and 106 malignant lymphomas) who had visited Aichi Cancer Center Hospital between March 1999 and December 2000. No DPYD CC individuals were found in either cases or controls. The frequency of DPYD TC genotype was 6.3% in control subjects and 5.9% in all case subjects (not significant). In a subgroup analysis, the frequency of TC genotype was highest in patients with gastric cancer (9.1%), followed by those with lung cancer (8.3%), with the lowest frequency in those with malignant lymphoma (1.9%). The gender- and age- adjusted odds ratios and 95% confidence intervals for the TC genotype of gastric cancer and malignant lymphoma were 1.52 (0.71-3.28) and 0.31 (0.71-1.34), respectively. Although prevalent cases were used, this study suggested that the influence of DPYD T85C posed only a limited risk for the six malignancies.
 ...
PMID:Polymorphism of dihydropyrimidine dehydrogenase (DPYD) Cys29Arg and risk of six malignancies in Japanese. 1737 78

We studied whether total gastrectomy for gastric cancer would affect the pharmacokinetics of 5-fluorouracil (5-FU) and its degradation products, such as dihydrouracil (FUH(2)) and alpha-fluoro-beta-alanine (FBAL), after oral administration of the fluorouracil derivative S-1, composed of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP; a dihydropyrimidine dehydrogenase inhibitor) and potassium oxonate. Blood and urine samples were obtained, both preoperatively and at least 2 weeks postoperatively, from six patients with advanced gastric cancers who were undergoing total gastrectomy. Plasma levels of tegafur, 5-FU, CDHP, potassium oxonate, FUH(2) and FBAL were measured prior to and at 1, 2, 4, 6 and 10 h after oral administration of 40 mg/m(2) S-1. The total amounts of 5-FU, FUH(2) and FBAL excreted into urine during the 24-h period after S-1 administration were also measured. Total gastrectomy significantly increased the maximum concentration and the area under the curve until 10 h after administration (AUC(1-10h)) of plasma 5-FU. The plasma AUC(1-10h) of CDHP was significantly higher than the preoperative value. In terms of clinical efficacy, the higher AUC(1-10h) of 5-FU after total gastrectomy may be beneficial to S-1 administered as adjuvant chemotherapy, and might be caused by the higher postoperative AUC(1-10h) of CDHP relative to preoperative values. However, the dose of S-1 for patients who have undergone total gastrectomy might be diminished to avoid severe adverse events and to continue the treatment for a long period.
 ...
PMID:Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and alpha-fluoro-beta-alanine after oral administration of S-1 following total gastrectomy. 1768 13

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.
 ...
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

Using laser-captured microdissection and a real-time RT-PCR assay, we quantitatively evaluated mRNA levels of the following biomarkers in paraffin-embedded gastric cancer (GC) specimens obtained by surgical resection or biopsy: excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), methylenetetrahydrofolate reductase (MTHFR), epidermal growth factor receptor (EGFR), and five other biomarkers related to anticancer drug sensitivity. The study group comprised 140 patients who received first-line chemotherapy for advanced GC. All cancer specimens were obtained before chemotherapy. In patients who received first-line S-1 monotherapy (69 patients), low MTHFR expression correlated with a higher response rate (low: 44.9% vs high: 6.3%; P=0.006). In patients given first-line cisplatin-based regimens (combined with S-1 or irinotecan) (43 patients), low ERCC1 correlated with a higher response rate (low: 55.6% vs high: 18.8%; P=0.008). Multivariate survival analysis of all patients demonstrated that high ERCC1 (hazard ratio (HR): 2.38 (95% CI: 1.55-3.67)), high DPD (HR: 2.04 (1.37-3.02)), low EGFR (HR: 0.34 (0.20-0.56)), and an elevated serum alkaline phosphatase level (HR: 1.00 (1.001-1.002)) were significant predictors of poor survival. Our results suggest that these biomarkers are useful predictors of clinical outcomes in patients with advanced GC.
 ...
PMID:Impacts of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase, and epidermal growth factor receptor on the outcomes of patients with advanced gastric cancer. 1823 Nov 4

S-1 has been reported good results in the treatment of stomach cancer. However, a DPD activity change has also been reported as one of the causes for a recurrence though some recurrence cases observing a state of tumor being unchanged continuously for more than 1 year. Therefore the urinary uracil value, which could simply be predicted in the DPD activity at the time of a recurrence after having administered S-1 for a long-term, was measured. And the urinary uracil value was examined whether it could become an index of recurrence compared with a healthy 5-person example as reference. In the result, a monthly difference in change of the urinary uracil values of the reference was small. However, the urinary uracil values in patients who were administered S-1 more than 6 months but recurred, were significantly lower comparing with the healthy 5-person example. We concluded from this study that the change in DPD activity due to an induction of DPD by 5-FU and metastasis of cancer caused the recurrence and lower a urinary value. The urinary uracil value reflecting DPD activity of the whole body could be used as an index of recurrence at the time of long-term dosage of S-1. Furthermore, a measurement of the urinary uracil value seems to be promising for estimation and evaluation of the cure.
 ...
PMID:[Study of a relationship between a change in the urinary uracil value after a S-1 long-term administration and the recurrence of stomach cancer]. 1863 22

Neoadjuvant chemotherapy has been a recent focus in the treatment for advanced gastric cancer. Although the preoperative chemotherapeutic regimen of S-1 and CDDP is regarded as effective, safe and well tolerable according to previous clinical study, we experienced a 74-year-old woman who suffered from life-threatening adverse events including severe myelosuppression during the neoadjuvant chemotherapy. Although the patient did not experience any severe adverse events during the first course of treatment, on day 18 of the second course of chemotherapy, she was hospitalized because of anorexia and severe dehydration, leading to following grade 4 leukopenia/neutropenia, bacteremia, and disseminated intravascular coagulation (DIC). She finally recovered from the life-threatening adverse events with intensive therapy and eventually had a distal gastrectomy. Clinicians need to be alert especially to renal dysfunction that induces severe myelosuppression during chemotherapy with S-1, which contains 5-chloro-2,4-dihydroxypyridine (CDHP), a renal excretory inhibitor of dihydropyrimidine dehydrogenase (DPD).
 ...
PMID:[Case report of gastric cancer patient who suffered life-threatening adverse events including severe myelosuppression during neoadjuvant chemotherapy with S-1 and CDDP combination]. 1879 15

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.
 ...
PMID:Decreased orotate phosphoribosyltransferase activity produces 5-fluorouracil resistance in a human gastric cancer cell line. 1902 Jul 40


<< Previous 1 2 3 4 5 6 7 8 9 Next >>