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)

In the present study, in order to evaluate the feasibility of personalized chemotherapy, a prospective randomized pilot study was performed in 30 advanced or recurrent gastric cancer patients. As we have demonstrated previously, the expressions of mRNA from tumor biopsy samples for seven molecular markers, i.e., dihydropyrimidine dehydrogenase (DPD), glutathione S-transferase (GST)-pi, beta-tubulin (tub), O6-methylguanine-DNA methyltransferase (MGMT), multiple drug-resistant protein (MRP)-1, NADPH/quinone oxidoreductase (NQO)-1, and cytochrome p450 (P450), were examined by reverse transcription-polymerase chain reaction (RT-PCR) analysis and therapy was recommended in a flow chart that depended on the level of expression of these predictive molecular markers. We chose 12 therapeutic plans, including best supportive care (BSC). We treated 15 patients according to the gene expression profiles, and the remaining 15 patients (controls) were treated without recommended regimens, and the therapy was continued after the expression profiles were checked. Interestingly, 11 of 26 lesions (42.3%) responded after treatment given according to gene expression analysis; however, no clinical response was detected in the control group. The prediction of the response, including resistance, was successful in 75.9% by the gene expression profiles. Moreover, the survival of the patients with the recommended treatment was better than that of patients without a recommended protocol. These results indicate that personalized treatment may be beneficial for gastric cancer chemotherapy and further randomized trials should be carried out in the future.
Gastric Cancer 2003
PMID:Future prospects of personalized chemotherapy in gastric cancer patients: results of a prospective randomized pilot study. 1277 25

To identify chemoresistance-related genes of gastric cancer, we utilized cDNA microarray technology. Thirty-five gastric cancer specimens surgically resected at our institute between 1998 and 1999 were studied for quantification of expression of 6300 genes by means of oligonucleotide microarray methods, and the results were evaluated in comparison with the chemoresistance of the specimens, which was determined by MTT (tetrazolium-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Inhibition rates (IR) were determined for cisplatin (DDP), 5-fluorouracil (5-FU), mitomycin C or doxorubicin. IR of 60% or more was regarded as sensitive to each agent, and IR of less than 40% was defined as resistant. Clustering was successfully completed for DDP, resulting in selection of 23 candidates as DDP-resistance-related genes, including vascular permeability factor, 2 membrane transporting subunits, and retinoblastoma-binding protein-1. In addition, further selection of DDP-resistance-related genes was performed according to these criteria: 1) Expression of the gene can be detected in more than 70% of resistant tumors. 2) Expression can be detected in less than 30% of sensitive tumors. 3) Expression in tumors is more than twice that of normal mucosa in more than 50% of specimens. Then, metallothionein-IG and heparin-binding epidermal growth factor-like growth factor (HB-EGF) were identified as candidate DDP-resistance-related genes. When known DDP-resistance-related genes were analyzed according to the MTT assay result, families of glutathione-S-transferase and cyclooxygenase-2 genes were also evaluated as resistance-related genes. For 5-FU resistance, dihydropyrimidine dehydrogenase and HB-EGF-like growth factor genes were also suggested to be resistance-related genes. The present study demonstrated that oligonucleotide microarrays can provide information regarding chemoresistance factors in cancer.
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PMID:Possible chemoresistance-related genes for gastric cancer detected by cDNA microarray. 1282 4

A total of 40 patients with advanced and recurrent gastric cancer in our hospital were treated with TS-1 alone, and the efficacy of treatment, survival time, and adverse effects were examined. TS-1 was administered with the usual dosage and dose regimen. Response to treatment included a complete response (CR) in 3 cases, partial response (PR) in 8 cases, no change (NC) in 10 cases, and progressive disease (PD) in 7 cases. The response rate was 39.3%, and among the 28 patients with evaluable lesions TS-1 produced a high response rate of 56.3% in 16 patients who had undergone prior therapy. The median survival time (MST) was 478 days in the 28 patients with evaluable lesions, excluding patients with peritoneal dissemination, and 283 days in the 12 patients with peritoneal dissemination. The outcome was markedly poorer in the patients with peritoneal dissemination than in the patients with evaluable lesions. The incidence of grade 3 or higher adverse effects was 20%, including two cases in which decreased dihydropyrimidine dehydrogenase (DPD) activity was suspected, and one case in which decreased dihydropyrimidinase (DHP) was suspected. Although the effect of TS-1 alone on gastric cancer is significantly superior to that of any conventional cancer drugs, the results of this study suggest that the antitumor effect varies with the site of the target lesions and according to whether the lesion is a remnant or recurrence.
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PMID:[A clinical results of TS-1 in advanced and recurrent gastric cancer in our hospital]. 1289 11

Conventionally adjustments of the dose of chemotherapeutic treatment could be uneffective in preventing toxicity and response variability. New strategies for individualization of treatment in cancer patients are becoming an emerging issue in the clinical practice. Pharmacogenetics is undoubtedly an important source of information in this respect deepening the complex correlation existing between individual genetic profile and the response to therapy in terms of toxicity and activity. Several polymorphisms, i.e. genetic mutations with a frequency > 1% in a given population, have been described for genes encoding proteins involved in the metabolism of the drugs employed in the treatment of gastric cancer. TS (thymidilate synthase) and DPD (dihydropyrimidine dehydrogenase) polymorphisms are implicated in the development of toxicity and in the efficacy of 5-fluorouracil (5FU). XRCC1 (X-ray cross-complementing group 1), ERCC1 (excision cross-complementing gene) and GSTP1 (glutathione S-transferase) have a role in the development of pharmacoresistance to platinum derivatives. MTHFR (5, 10 methylenetetrahydrofolate reductase) C677T polymorphism is important in methotrexate (MTX) metabolism. UGT1A1 (uridine diphoshate-glucuronosyltransferase 1A1) is involved on irinotecan metabolism. MRP2 (multi-drug resistance associated protein) and MDR1 (multi-drug resistance gene) are involved in irinotecan as well as anthracyclines transport. In conclusion, the clinical applications of pharmacogenetics could represent a new insight to accurately determine the proper drug and dose to be used in each individual patient.
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PMID:Pharmacogenetics of stomach cancer. 1291 84

The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg m(-2) day(-1) for 5 days. After a washout period of 9 days, the patients received two divided doses daily for 28 days. S-1 was administered orally at about 0900 and 1900 hours. The daily dose of S-1 in terms of tegafur was 80 mg day(-1) in patients with a body surface area (BSA) of <1.25 m(2), 100 mg day(-1) in those with a BSA of >or=1.25 m(2) to <1.5 m(2), and 120 mg day(-1) in those with a BSA of >or=1.5 m(2). Plasma concentrations of 5-FU and F-beta-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition (pharmacodynamic analysis) in the same patients on days 1-5 of PVI of 5-FU and on days 1-5 of oral S-1. The area under the curve (AUC(0-10 h)) of 5-FU on day 5 was 728+/-113 ng h ml(-1) for PVI of 5-FU and 1364+/-374 ng h ml(-1) for S-1. The median 5-FU PVI : S-1 ratio of the AUC(0-10 h) of 5-FU was 1.9. The AUC(0-10 h) of FBAL on day 5 of PVI of 5-FU was 9465+/-3225 ng h ml(-1), AUC(0-10 h), as compared with 1725+/-605 ng h ml(-1) on day 5 of S-1 treatment. The AUC(0-10 h) of uracil on day 5 was 252+/-60 ng h ml(-1) with PVI of 5-FU and 12 582+/-3060 ng h ml(-1) with S-1. The AUC(0-10 h) of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.
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PMID:Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil. 1294 10

The efficacy and safety of the oral fluoropyrimidine TS-1, which contains a dihydropyrimidine dehydrogenase (DPD) inhibitor, were examined in fifty-five patients with gastric cancer. The patients were divided into 28 with measurable cancer lesions (TUM group) and 27 without them (ADJ group). The total number of courses was 164 (mean: 5.9 courses) in the TUM group and 146 (mean; 5.4 courses) in the ADJ group. The response rate in the TUM group, excluding three patients who could not be evaluated because of incomplete administration, was 40% (CR: 4, PR: 6, NC: 6, PD: 9). Among responders, the mean number of courses to response was 2.2 and the median survival time (MST) was 21.7 months. In terms of safety, adverse reactions appeared in forty-five patients (82%) and the incidence was higher in the ADJ group. Major toxicities were leukopenia (38%), anorexia (27%), increased total bilirubin concentration (25%) and diarrhea (24%). Adverse reaction of grade 3 was found in only three patients (5.5%) and there were no drug-related deaths. In conclusion, TS-1 is safe and effective if attention is given to biweekly examinations for the development of adverse reactions.
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PMID:[Efficacy and safety of novel oral fluoropyrimidine anticancer drug, TS-1 for advanced and recurrent gastric cancer patients]. 1451 9

To elucidate the mechanism of the enhanced antitumour activity of S-1 (1 M tegafur, 0.4 M 5-chloro-2, 4-dihydroxypyridine, and 1 M potassium oxonate) in terms of the phosphorylation and degradation pathways of 5-fluorouracil (5-FU) metabolism, we investigated tumoral thymidylate synthase (TS) content, dihydropyrimidine dehydrogenase (DPD) activity, the TS inhibition rate (TS-IR), and 5-FU incorporated into RNA (F-RNA) in four human gastric cancer xenografts (MKN-28, MKN-74, GCIY and GT3TKB) and compared the results obtained with S-1 with those obtained with 5-FU and UFT (1 M tegafur, 4 M uracil). 5-FU was administered intraperitoneally (i.p.) to mice at a dose of 50 mg/kg, three times, on days 0, 4 and 8. S-1 and UFT were administered orally at doses of 10 and 24 mg/kg, respectively, once a day, for 9 consecutive days. Antitumour activity was evaluated as the maximum inhibition of tumour growth in each animal. S-1 showed a better antitumour activity than 5-FU and UFT in tumours with a high DPD activity (GCIY and GT3TKB). There were inverse correlations between the antitumour activity and both TS content and DPD activity in the 5-FU and UFT groups. However, no such correlations were observed in the S-1 group. In GCIY and GT3TKB xenografts, TS-IR was significantly higher in the S-1 group than in the 5-FU or UFT groups. In GT3TKB xenografts, the F-RNA level was significantly higher in the S-1 group than in the 5-FU or UFT groups. The superior cytotoxicity of S-1 appears to be attributable to both an increased inhibition of DNA synthesis and an enhanced blockade of RNA function against tumours with a high DPD activity.
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PMID:Superior antitumour activity of S-1 in tumours with a high dihydropyrimidine dehydrogenase activity. 1455 32

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m(-2) b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m(-2) depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m(-2), because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m(-2). In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1-8). The incidences of severe (grades 3-4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9-90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.
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PMID:Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer. 1467 96

We studied the relation between clinicopathological factors and dihydropyrimidine dehydrogenase (DPD) activity in gastric and colorectal carcinomas. Specimens obtained by surgery from 27 gastric and 17 colorectal carcinomas and their normal mucosa were examined. The levels of DPD activity in the gastric carcinomas and their normal mucosa were significantly higher than those in colorectal carcinomas and their normal counterparts, respectively (both P's < 0.0001). The gastric carcinomas had significantly higher DPD activities than their normal mucosa (P = 0.028), but the colorectal carcinomas did not. Among the clinicopathological factors, which included invasion/metastatic status and staging, the only effect was that of the histological differences of gastric cancer on DPD activity. That is, the level of DPD activity of the histologically undifferentiated gastric carcinoma was significantly higher than that of the differentiated type. No prognostic predictive values of DPD were recognized in either gastric and colorectal cancer. In conclusion, the higher DPD activity in gastric cancer than colorectal cancer may be due to the higher DPD activity in the background mucosa of origin, and the higher population of undifferentiated type of histological classification, compared to the colorectal counterparts.
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PMID:Differences in dihydropyrimidine dehydrogenase activities between gastric and colorectal cancer. 1499 36

A second-line chemotherapy for advanced gastric cancer has not been established. We report a case of good response in a 39-year-old woman who had recurrent pleural effusion and positive cytology of type 4 gastric cancer and was treated with TS-1, a DPD inhibitory fluoropyrimidine, in combination with weekly taxane. After a partial response for type 4 gastric cancer from the treatment with 2 courses of TS-1 plus low-dose cisplatinum (CDDP), followed by outpatient chemotherapy with TS-1 alone or TS-1 plus weekly CDDP, left pleural effusion appeared and CA19-9 increased during the 7th course of the chemotherapy. Cytology of the effusion was class IV. The patient was treated with a course of TS-1 (120 mg/day, day 1-21) plus paclitaxel (50 mg/m2, day 1, 8) followed by 2 week washout. In the following courses, paclitaxel was replaced with docetaxel (30 mg/m2, day 1 and 8) and the course was continued in the outpatient setting. After 2 courses, the left pleural effusion disappeared and remained absent after 6 courses. Gastric biopsy showed no cancer cells and abdominal CT showed no recurrence. Serum CA19-9 doubled 1 week after taxane treatment and decreased gradually week by week during the course. This case suggests that a combination of TS-1 and taxane is effective against recurrent pleural effusion of advanced gastric cancer and useful as a second-line chemotherapy.
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PMID:[A case of recurrent pleural effusion and positive cytology of advanced gastric cancer treated by TS-1 plus weekly taxane as second-line chemotherapy]. 1504 61


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