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)

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

Molecular markers involved in DNA repair can help to predict survival in gastric cancer patients treated with 5-FU plus platinum chemotherapy. Excision repair cross-complementing 1 (ERCC1) and thymidylate synthase (TS) mRNA expression levels were assessed in advanced gastric cancer tumour samples using real-time quantitative PCR in 76 patients treated with a modified FOLFOX (biweekly oxaliplatin plus 5-FU and folinic acid) regimen. Median survival time in patients with low ERCC1 levels was significantly longer than in those with high levels (15.8 vs 6.2 months; P<0.0001). Patients with high TS levels had longer survival than those with low levels (12.2 vs 10.1 months; P=0.01). Forty-eight patients with low ERCC1 and high TS levels had a median survival of 16.1 months (P<0.0001). The hazard ratio for patients with high ERCC1 expression was 9.4 (P<0.0001). In patients with high mRNA levels of ERCC1, alternative chemotherapy regimens should be considered.
 ...
PMID:ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen. 1836 36

S-1 has been considered to be a key drug in the treatment of advanced gastric cancer in Japan as a standard option of chemotherapy. Interindividual variation in the enzymes of the S-1 metabolic pathway can affect the extent of S-1 metabolism and impact the efficacy of S-1-based chemotherapy. In this review, the role of the "candidate" genetic factors affecting the therapeutic efficacy of S-1 is discussed with a special emphasis on polymorphism and gene expressions involved in the S-1 metabolic pathway, including CYP2A6, thymidylate synthase, thymidine phosphorylase, and orotate phosphoribosyltransferase. The predictive values of these candidates might be overcome with drugs combined with S-1. Pharmacogenetic studies based on a "global" approach by DNA microarray are promising to identify gastric cancer patients with both survival benefit and clinical benefit more accurately than those based on the "candidate" approach, especially for S-1 combination therapy. Large and controlled studies are needed to justify changes in the chemotherapeutic strategies, from "one-size fits all" to "tailor-made."
 ...
PMID:Challenges in predicting the clinical outcome in S-1-based chemotherapy for gastric cancer patients. 1855 29

5-Fluorouracil (5-FU) has been the most widely accepted and studied chemotherapeutic agent, and many combination chemotherapeutic regimens have been reported. However, until recently, a standard regimen for metastatic gastric cancer had not been established. The combination of S-1 and cisplatin is a good candidate as a standard first-line regimen for metastatic gastric cancer. On the other hand, interest in biochemical modulation has become wide spread recently. The low level of dihydropyrimidine denhydrogenase (DPD), thymidylate synthase (TS) activities, and a high level of orotate phosphoribosyl-transferase (OPRT) activity enhance the antitumor effect of 5-FU and S-1. Docetaxel is one of the agents that modulate these enzyme expressions and activities. Moreover, the response rate of combination therapy of docetaxel and S-1 for metastatic gastric cancer was 56.3% and median survival time was 14.3 months in a phase II study, showing it to be a good candidate for a new standard regimen for gastric cancer. A phase III collaborative study, START (S-1 and Taxotere for advanced gastric cancer randomized phase III trial), is now under way in Japan and Korea.
 ...
PMID:Challenge for a better combination with basic evidence. 1855 30

Studies investigating the association of polymorphisms in the 5'-untranslated regions (5'UTR) and 3'-untranslated regions (3'UTR) of thymidylate synthase with gastric cancer susceptibility and sensitivity to fluoropyrimidine-based chemotherapy report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. This meta-analysis included ten studies, which included 1,730 gastric cancer cases and 1,843 controls. The combined results based on all studies showed that there was no significant difference in genotype distribution of 5'UTR or 3'UTR between gastric cancer and noncancer patients. When stratifying for race, we found that: (1) among Asians, patients with gastric cancer had significantly higher frequency of 2R/2R of 5'UTR than did noncancer patients, and (2) among Caucasians, patients with gastric cancer had significantly lower frequency of ins6/ins6 and higher frequency of ins6/del6 of 3'UTR than did noncancer patients. No significantly different response rate or survival of gastric cancer with fluoropyrimidine-based chemotherapy were observed with genotype distribution of 5'UTR or 3'UTR among Caucasians or Asians. This meta-analysis suggests that polymorphisms in the 5'UTR and 3'UTR of thymidylate synthase may be associated with gastric cancer susceptibility, but are not correlated with sensitivity of gastric cancer to fluoropyrimidine-based chemotherapy.
 ...
PMID:Polymorphisms of thymidylate synthase in the 5'- and 3'-untranslated regions and gastric cancer. 1898 79

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

The aim of this study was to analyse the impact of epidermal growth factor receptor (EGFR), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), aurora kinase (ARK) A/B, and excision repair cross-complementing gene 1 (ERCC1) on the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin (FP) after curative gastric resection. Normal and cancer tissue were separately obtained from gastrectomy samples of 153 patients with AJCC stage III-IV (M0) who subsequently treated with adjuvant FP chemotherapy. TS, DPD, TP, ERCC1, and ARK proteins were measured by immunohistochemistry (IHC). EGFR expression was investigated using a standardized IHC with the EGFR PharmDx assay. Amplification of EGFR gene was analysed using fluorescent in situ hybridisation (FISH). In multivariate analysis, stage, ratio of positive to removed lymph nodes, and EGFR expression were significant prognostic factors for overall survival. Patients with higher EGFR expression had better overall survival than those with lower expression (relative risk: 0.475 (95% confidence interval, 0.282-0.791, P=0.005). Low EGFR expression might be a predictive marker for relapse in curative resected stage III-IV (M0) gastric cancer patients who received adjuvant FP chemotherapy.
 ...
PMID:Biomarker analysis in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant 5-fluorouracil and cisplatin chemotherapy: epidermal growth factor receptor (EGFR) associated with favourable survival. 1925 93

A phase III trial of S-1 plus cisplatin (SP) versus S-1 alone, for first-line treatment of advanced gastric cancer (SPIRITS trial), has shown that overall survival was better in patients treated with SP than with S-1 alone. In the present retrospective biomarker study, we aimed to develop a methodology to identify the patients with advanced gastric cancer who would respond better to S-1 alone than SP. We studied 120 patients who received S-1 alone or SP for first-line chemotherapy for advanced gastric cancer, and quantitatively evaluated mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), dihydropyrimidine dehydrogenase, vascular endothelial growth factor-A, and epidermal growth factor receptor in paraffin-embedded specimens of primary tumors. Multivariate survival analysis in patients who received S-1 monotherapy (66 patients) demonstrated that low TP expression (hazard ratio: 2.55 (95% CI: (1.33 to 4.89)), low TS (2.71 (1.36 to 5.37)), and high OPRT (0.33 (0.13 to 0.86)) were significant predictors of long overall survival. In patients with lower expression of both TP and TS (n = 23) than their cutoff values, the S-1 alone group (n = 15) had longer overall survival than the SP group (n = 8; median overall survival, 18.2 months vs. 9.4 months), whereas the frequency of overall adverse events in the S-1 alone group tended to be lower than that in SP group. Our results suggest that these biomarkers are useful for selection of patients with advanced gastric cancer in whom treatment with S-1 alone will yield survival benefit.
 ...
PMID:Impacts of fluorouracil-metabolizing enzymes on the outcomes of patients treated with S-1 alone or S-1 plus cisplatin for first-line treatment of advanced gastric cancer. 1958 1

Chemotherapy plays an important role in the treatment of gastric cancer both in adjuvant or advanced settings. Recent randomized trials in Japan have proved that S-1, a novel fluoropyrimidine derivative, and cisplatin are the most promising agents. However, both the efficacy and toxicity of a given regimen vary widely among patients due to the inherited variability of genes that involve drug anabolism and catabolism. A narrow therapeutic index of antitumor agents, i.e. a given regimen being too toxic and/or less effective to some segment of patients, prevents the overall improvement of treatment outcomes. Pharmacogenetics, a research field elucidating genetic polymorphism in drug metabolizing enzymes, may contribute to identifying patients who benefit from chemotherapy or who will experience life-threatening toxicity. There are several crucial enzymes identified involving anabolism and the catabolism of fluoropyrimidine and cisplatin, including dihydropyrimidine dehydrogenase, thymidylate synthase, orotate phosphoribosyl transferase, glutathione S transferase, and excision repair cross complementary group. Various polymorphisms and ethnic variabilities of these genes have been elucidated. This review highlights variations within biological functions, detection systems, and possible clinical applications of these enzymatic polymorphisms. This knowledge provides a tool to determine an optimum regimen according to the patient's drug metabolizing characteristics. This stance will contribute to establishing individualized therapies for gastric cancer, which offers superior efficacy with a minimal chance of severe toxicity.
 ...
PMID:Pharmacogenetics of fluoropyrimidine and cisplatin. A future application to gastric cancer treatment. 1963 79

Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The present study investigated the association between germline genetic polymorphisms and the treatment outcome of cetuximab plus modified leucovovin, fluorouracil, and oxaliplatin (FOLFOX)6 chemotherapy in advanced gastric cancer (AGC). DNA from peripheral blood mononuclear cells of 38 patients enrolled in a phase II study of cetuximab plus modified FOLFOX6 were analyzed for 16 polymorphisms in eight genes (EGFR, epidermal growth factor, transforming growth factor-alpha (TGFA), thymidylate synthase, excision repair cross-complementation group 1, Xeroderma pigmentosum group D, and fragment c gamma receptors (FCGR)2A and 3A). The EGFR intron 1 CA repeat polymorphism was associated with survival. Twenty-one patients had low repeats (sum of both alleles <or=37), and 17 patients had high repeats (sum >or=38). Patients with low CA repeats had longer progression-free survival (adjusted hazard ratio [HR] 0.42 [95% confidence interval [CI] 0.19-0.96], P = 0.040) and overall survival (adjusted HR 0.40 [95% CI 0.16-0.99], P = 0.048) compared with patients with high CA repeats. In addition, the tumor EGFR expression was higher in patients with a lower number of CA repeats. The association between the CA repeat status and survival was not found in a separate cohort of AGC patients (n = 68) treated only with modified FOLFOX6. These results suggest that the EGFR intron 1 CA repeat polymorphism could be a useful, predictive biomarker of cetuximab efficacy in AGC and merits further investigation in randomized studies.
 ...
PMID:Epidermal growth factor receptor intron 1 CA dinucleotide repeat polymorphism and survival of advanced gastric cancer patients treated with cetuximab plus modified FOLFOX6. 2004 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>