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)

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

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

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

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

UCN-01, a protein kinase C/cyclin-dependent kinase inhibitor, suppressed thymidylate synthase (TS) protein expression in a dose-dependent manner with near complete suppression at 1 microM after a 24-h exposure in human gastric cancer cell line SK-GT5. Other protein kinase C/cyclin-dependent kinase inhibitors, including flavopiridol and safingol, had a similar effect on TS protein expression, but to a lesser degree. Moreover, UCN-01 repressed the induction of TS after 5-fluorouracil (FU) exposure by 90-95% and significantly enhanced the induction of apoptosis by FU from 4-8% with either FU or UCN-01 alone to 46+/-1% (P < 0.005 versus either single drug, reverse sequence, or the combination) when UCN-01 was given after FU. The effect of UCN-01 on TS was associated with a dose-dependent suppression of the E2F-1 protein, a transcriptional activator of TS. Northern blot analysis revealed that TS mRNA levels decreased gradually as the concentration of UCN-01 increased, but that E2F-1 mRNA levels remained relatively unchanged. UCN-01 may provide a novel way to enhance cellular sensitivity toward FU by means of suppressing TS expression mediated mainly by down-regulation of E2F-1.
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PMID:UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. 974 40

The immunohistochemical expression of thymidylate synthase (TS) and thymidine phosphorylase (TP) was investigated in 116 of early gastric cancer, in order to know whether or not these reflect malignity in an early stage. The materials conditioned on early gastric cancer with submucosal invasion and over 1 cm2 in size, were 57 with and 59 without lymph node metastasis. They were divided into two by the depth of invasion. The expressions of TS and TP in these group were compared with corresponding histopathological findings. Overall expressions of TS and TP were 54.3% and 34.5%, respectively. The TS-expression was not related with the depth of invasion and lymph node metastasis. The TP-expression, however, showed significant difference between with and without lymph node metastasis, and was so on the depth of submucosal invasion in the group without the nodal metastasis. Multivariate analysis showed that mucosal spread bordering 4 cm2 in size (p = 0.024) and lymphatic permeation (p = 0.099) in TS-expression, and lymph node metastasis (p = 0.041), submucosal invasion (p = 0.076) and venous permeation (p = 0.111) in TP-expression were the noticeable factors regarding to their high expression rates. Although these results were considered not to exceed gastric resection on the prognosis, they might be applicable as one of the indicators in postoperative follow-up on the minor resection of early gastric cancer such as EMR or local resection.
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PMID:[The expression of thymidylate synthase and thymidine phosphorylase in the early-stage of gastric cancer]. 1006 95

Phase III studies have shown irinotecan prolongs survival significantly when compared with either best supportive care or best infusional 5-fluorouracil (5-FU)-based chemotherapy in patients with 5-FU-resistant colorectal cancer. Phase I/II studies are investigating the combination of irinotecan with 5-FU, with thymidylate synthase inhibitors, notably raltitrexed, and with the oral fluoropyrimidines. Preliminary results suggest irinotecan and raltitrexed can safely be combined in the clinic and that this combination is active. The combination of irinotecan with the oral fluoropyrimidines also has produced promising results. A phase I study of irinotecan plus 5-FU/folinic acid showed high activity in first-line metastatic disease and further trials using the doses of 80 mg/m2 irinotecan plus 2 g 5-FU weekly are recommended. The combination of irinotecan with the De Gramont 5-FU regimen is feasible and active in patients with 5-FU-resistant metastatic disease. Alternating exposure to irinotecan and 5-FU may be as active as either treatment alone, and has been associated with overall response rates (ORRs) greater than 30% and encouraging median survival. The combination of irinotecan with oxaliplatin is also feasible and levels of response rates are in the region of 50% (especially with a 2-weekly administration schedule). In patients with advanced gastric cancer (including those with pretreated disease) ORRs of around 50% have been reported following administration of either cisplatin plus irinotecan or cisplatin plus docetaxel.
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PMID:Clinical advances with topoisomerase I inhibitors in gastrointestinal malignancies. 1063 Mar 62


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