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)

Knowledge of population thymidylate synthase (TS) levels in malignant tumors and normal tissues is essential for the use of TS as a predictor for 5-fluorouracil treatment. Tumor tissue TS levels in fresh frozen surgical biopsies from 136 patients with gastrointestinal or breast cancer, not previously subjected to chemotherapy, were analysed by [3H]FdUMP radioligand binding assay. TS levels were 2.4 +/- 0.31 pmol/g in liver metastases of colorectal cancer (n = 87), 4.2 +/- 1.0 pmol/g in primary colorectal cancer (n = 13), 2.7 +/- 0.93 pmol/g in gastric cancer (n = 13), 3.1 +/- 1.7 pmol/g in pancreatic cancer (n = 10), 3.4 +/- 1.4 pmol/g in breast cancer (n = 13) and 0.58 +/- 0.075 pmol/g in normal liver parenchyma (n = 24). TS levels were significantly higher in malignant tumor tissues compared to normal liver parenchyma.
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PMID:Thymidylate synthase in advanced gastrointestinal and breast cancers. 869 63

To investigate quantitative methods for assessing the response to preoperative downstaging chemotherapy (PDC), the immunocytochemical expression of proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) as well as a pharmacologic study of the rate of thymidylate synthetase inhibition (TSIR) were studied in resected specimens obtained from patients with advanced gastric cancer. Fifty-one patients with advanced gastric cancer who received PDC (30 with 5-fluorouracil peroral administration and the other 21 with intravenous administration of 5-fluorouracil and cisplatin) were studied. The labeling index of PCNA (PCNA-LI) and BrdU were measured. The PCNA suppression (PCNA-S), which was measured by both the values of prechemotherapeutic PCNA-LI in endoscopically biopsied specimens and postchemotherapeutic PCNA-LI in resected specimens, was also examined. TSIR was measured by a protein-bound radiochemical method. We compared the above-mentioned parameters with the histopathological response to PDC according to the General Rules for Gastric Cancer Study. In the patients with peroral 5-flurorouracil, a stepwise regression analysis showed that TSIR is a significantly effective for determining the histopathological response to PDC. In the patients with 5-fluorouracil and cisplatin, PCNA-S was the most effective indicator of the histopathological response to PDC, as shown by a stepwise regression analysis. The present study thus showed that both TSIR and PCNA-S were effective additional indicators of the histopathological response to PDC.
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PMID:Histopathological response to preoperative chemotherapy including 5-fluorouracil additionally assessed by immunocytochemical and pharmacologic parameters in patients with advanced gastric cancer. 884 Apr 28

ZD1694 (Tomudex), a quinazoline folate analogue, is a potent and selective thymidylate synthase inhibitor. A phase II trial was undertaken to determine the efficacy and toxicity of ZD1694 in patients with advanced, measurable gastric adenocarcinoma. ZD1694, 3.0 mg/m2, was administered as a 15 min intravenous infusion every three weeks. Tumor measurements were obtained for response assessment every six weeks. Clinical examinations, adverse event assessments, and clinical laboratory tests were performed every three weeks. Thirty-three patients were enrolled. There were no objective responses to ZD1694. In general, treatment was well-tolerated. Grade 3 and 4 toxicities were infrequent, and included mucositis, nausea and vomiting, leukopenia, thrombocytopenia, and elevations of liver enzymes. Mild to moderate asthenia was common. Toxicities with ZD1694 were reversible and manageable. In conclusion, ZD1694 has an acceptable toxicity profile but shows no antitumor activity in patients with advanced gastric cancer.
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PMID:Phase II study of ZD1694 in patients with advanced gastric cancer. 893 86

A new method of biochemical modulation of 5-fluorouracil (5-FU) with 3'-azido-3'-deoxythymidine (AZT) was studied experimentally. Nude mice transplanted with cells of the human gastric cancer cell line MKN28 were divided into 4 groups, i.e., control, 5-FU, AZT, and 5-FU plus AZT, and the antitumor activities were compared. Based on the assessment of tumor volume, significant suppression of tumor growth was observed in the 5-FU and 5-FU plus AZT groups (P<0.05, P<0.01, versus control, respectively). The thymidylate synthase (TS) inhibition rate, an index of inhibition of the de novo pathway, was significantly higher in the 5-FU and 5-FU plus AZT groups than in the control group (P<0.01), but it did not differ from the control in the AZT group. TS-bound FdUMP tended to be higher in the 5-FU plus AZT group than in the 5-FU group. The activity of thymidine kinase (TK) and the uptake ratio of 5-bromo-2'-deoxyuridine (BrdU), indices of salvage pathway activity, were significantly lower in the AZT and 5-FU plus AZT groups than in the control group (TK, P< 0.05, P < 0.01; uptake ratio of BrdU, P < 0.01, P < 0.05, respectively). There were slight losses of body weight in the 5-FU and 5-FU plus AZT groups compared with that in the control group, but no difference between the AZT and control groups in weight loss. These findings suggest that addition of AZT plays an important role in potentiating the antitumor activity of 5-FU through both blockage of a compensatory increase of activity in the salvage pathway and also an increase in TS-bound FdUMP, and has no adverse effects. Thus, the combination of 5-FU and AZT could be useful as a new modality in gastric cancer chemotherapy.
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PMID:Experimental studies on potentiation of the antitumor activity of 5-fluorouracil with 3'-azido-3'-deoxythymidine for the gastric cancer cell line MKN28 in vivo. 904 2

A number of new cytotoxic agents are currently being assessed for the treatment of gastro-intestinal cancers. Colorectal cancer has been successfully treated with several direct thymidylate synthase inhibitors, oral 5-fluorouracil analogues, irinotecan, and oxaliplatin, alone and in combination regimens. Upper gastro-intestinal malignancies are also proving responsive to combinations including irinotecan and the taxanes. Pancreatic cancer, while remaining relatively chemoresistant, is proving treatable with the new direct thymidylate synthase inhibitors, docetaxel, and gemcitabine, improvements in quality of life being an important outcome. New strategies of treatment delivery are also proving beneficial. Neo-adjuvant chemotherapy is well tolerated for the treatment of gastric cancer and results in tumour downstaging. Randomized trials will show whether this translates into a survival advantage. Combination chemoradiation for oesophageal, pancreatic, and rectal cancers also appears to be an effective strategy. Biological therapies including hormonal manipulation, immunotherapy, angiogenesis inhibition, and gene-directed therapies are the subjects of intensive research at present, with many approaches being applied in early clinical trials. These have demonstrated the tolerability of many of these treatments with evidence for activity in some cases.
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PMID:New approaches to the treatment of gastro-intestinal cancer. 943 95

Human tumors are generally methionine (MET)-dependent in that their growth is inhibited by MET-depletion down to levels that will still allow normal cell growth. The differential effect of methionine depletion on tumor and normal cells has suggested that methionine depletion may be able to modulate many and possibly all classes of cancer drugs. In this report, we determined if MET-depletion could modulate 5-fluorouracil (5-FU) efficacy on the human gastric cancer xenograft, SC-1-NU in nude mice. The tumor-bearing mice were treated with a MET-free diet and intraperitoneal administration of 5-FU at a dose of 30 mg/kg given for four cycles. MET depletion enhanced the antitumor activity of 5-FU by approximately two-fold with statistical significance of p < 0.05. The MET-free diet increased intratumoral thymidylate synthetase inhibition early after 5-FU administration; Therefore, MET-depletion was thought to increase the 5-FU antitumor activity by modulating intratumoral folate metabolism. The data in this report suggest the high clinical potential of methionine depletion, combined with 5-FU and leucovorin on refractory tumors such as stomach cancer.
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PMID:Methionine-depletion modulates the efficacy of 5-fluorouracil in human gastric cancer in nude mice. 949 35

Low-dose therapy consisting of cisplatin plus 5-fluorouracil was given to 20 patients with advanced gastric cancer, and specimens were obtained to evaluate levels of 5-fluorodeoxyuridine (FdUMP) and thymidylate synthase (TS), indices of DNA, and proliferating nuclear cell antigen (PCNA). There was a significant correlation between the levels of FdUMP, total TS and free TS in cancer and in normal gastric mucosa, respectively. Total TS of cancer was higher than that of normal tissue, at 5.3 +/- 4.8 and 3.4 +/- 2.2 pmol/g, respectively. On the other hand, there was no relationship nor difference between The TSIR ratio of cancer and normal mucosa. The FdUMP levels of far advanced cancer showed a tendency to be lower than those of the less advanced one, especially in liver metastasis. The total TS was higher in intestinal type and in INF alpha or beta. The free TS was higher in invasive type, liver metastasis and curability C. The TSIR ratio showed a tendency to be lower in far advanced cases, such as invasive type and INF gamma. The correlation between DNA index and TS values and between PCNA labeling index and TS values were good. These results suggest that TS levels would be a predictor for malignant potential as well as for chemosensitivity.
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PMID:[Effect of low-dose CDDP/5-FU therapy on thymidylate synthase content]. 958 51

We investigated the utility of examining biological markers to predict chemoresponse and survival. The subjects consisted of 39 unresectable gastric cancer patients treated with a combination of 5-fluorouracil and cis-platinum. The expression of p53, bcl-2, thymidylate synthase (TS), glutathione S-transferase pi (GST-pi), and vascular endothelial growth factor (VEGF) in the formalin-fixed biopsy samples of primary tumors before chemotherapy was examined immunohistochemically. The positive rate for VEGF, bcl-2, TS, p53, and GST-pi was 51, 10, 46, 38, and 69%, respectively. VEGF-positive cases showed a higher response rate than did negative cases (11 of 20 versus 2 of 19 cases; P = 0.0057). The cases that were negative for p53, TS, bcl-2, and GST-pi were more likely to respond to chemotherapy than the cases that were positive for these markers. The 10 cases having 4 or 5 favorable phenotypes (VEGF positive, p53 negative, bcl-2 negative, TS negative, and GST-pi negative) survived longer than the remaining 29 cases (P = 0.0069). Multivariate analysis revealed that the number of favorable phenotypes (> or = 4 versus < or = 3) had a greater impact on survival than performance status (0 versus 1 or 2), age (> 60 years versus < or = 60 years), macroscopic type (scirrhous versus nonscirrhous), histological type (intestinal versus diffuse), or tumor extent (locally advanced versus metastatic). Immunohistochemical examination of biological markers in biopsy samples may be useful in predicting the clinical outcome of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum.
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PMID:Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. 962 64

Currently, biochemical modulation for 5-fluorouracil (5-FU) is one of the most successful chemotherapy for both colo-rectal and gastric cancer. The purpose of this study is to evaluate the significance of measuring intratumoral thymidylate synthetase (TS) and folate (FH4) levels as predictive parameters for the successful treatment. Samples were collected from 16 advanced colo-rectal and 21 advanced gastric cancer. TS and tetrahydrofolate levels in the specimens were measured by binding assay. Results showed that there were no significant difference in TS levels between the different pathologic types of carcinoma. On the other hand, well (3.94 +/- 1.75 p mol/g) and moderately (5.95 +/- 2.69 p mol/g) differentiated carcinoma showed lower FH4 levels compared to poorly differentiated carcinoma (9.58 +/- 5.27 p mol/g). In conclusion, biochemical modulation by cisplatin or leucovorin, which elevates intratumoral folate levels, is more needed for well and moderately differentiated carcinoma. Finally, measuring TS levels can also be important because two cases who responded to cisplatin/5-FU chemotherapy showed low TS levels compared to the others who had lower response.
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PMID:[The intratumoral levels of thymidylate synthetase and folate in gastric and colon cancer]. 967 79

It has been hypothesized that intratumoral thymidylate synthase (TS) gene expression might be used to select therapy for patients with disseminated colorectal cancer. We recently reported the results of a clinical trial in 46 patients with disseminated or recurrent colorectal cancer testing whether expression of TS within the primary tumor, as assessed by quantitative polymerase chain reaction (PCR) methodology, would predict the responsiveness of that cancer of fluoropyrimidine-based therapy. This trial demonstrated that intratumoral TS/beta-actin messenger RNA (mRNA) ratio can accurately predict which metastatic colorectal tumors will be resistant to a leucovorin-modulated 5-FU infusion and which have a high likelihood of responding to such a regimen. Results of other studies of adjuvant therapy in gastric cancer and colorectal cancer also indicated that TS expression within the tumor is predictive of response of 5-FU-based therapy. It may be possible to use this parameter prospectively to decide which patients should receive fluorinated pyrimidine therapy: Patients whose tumors express low TS levels would be likely to benefit from such therapy, whereas limited preliminary data suggest that patients whose tumors express high TS levels may benefit from irinotecan (CPT-11[Camptosar]).
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PMID:Thymidylate synthase as a predictor of response. 972 90


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