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)

In a previous clinical study, sequential methotrexate and 5-fluorouracil has shown improved efficacy for treating advanced gastric cancer of the poorly differentiated type. In this study, we investigated whether difference in the levels of thymidylate synthetase (TS) and thymidine kinase (TK) activities in gastric cancer tissue account for selectivity of the treatment. Activity of TS was higher in 19 cases of the poorly differentiated type than in 16 cases of the well differentiated type (P < 0.02), whereas TK activity was lower in the poorly differentiated type than in the well differentiated type (P < 0.01). Thus, the TS/TK ratio was significantly higher in poorly differentiated gastric cancers than in well differentiated cancers (P < 0.001). These results suggest that a greater dependence upon the de novo pathway of pyrimidine synthesis in poorly differentiated gastric carcinomas may enhance the efficacy of sequential methotrexate and 5-fluorouracil treatment.
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PMID:Activities of thymidylate synthetase and thymidine kinase in gastric cancer. 134 Dec 54

We evaluated antitumor effect histologically and assayed the tissue levels of 5-fluorouracil (5-FU) and thymidylate synthase (TS) activity using surgical specimens obtained from the patients with rectal cancer, who were given tegafur suppositories prior to surgery. The antitumor effect was evaluated histologically according to classification of the general rules for the gastric cancer study (Japanese Research Society for Gastric Cancer). In 39 patients, 16 tumor specimens revealed no effect (grade-0), 22 tumors grade-1 effect, and one was not evaluable because of the severe inflammatory changes. In 23 of these patients, resected specimens were available for the assay. 5-FU levels in cancer tissues were significantly higher than those in normal tissues, and TS inhibition rates (TSIR) were almost identical, averaging around 20%, in both cancer and normal tissues. Comparing the 5-FU levels and TS activity according to the histological effects (i.e.: 'grade-0' vs 'grade-1'), the 5-FU levels in the tumors achieved grade-1 were significantly higher than in the tumors showed 'grade 0' (p less than 0.01), and TSIR in the former were relatively greater than in the latter (p = 0.053). It is suggested that both tissue levels of 5-FU and TSIR may be useful parameters to predict the anti-tumor effect against rectal cancer after administration of 5-FU and its derivatives.
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PMID:[Neo-adjuvant chemotherapy with tegafur suppository for rectal cancer--evaluation of the antitumor effects, tissue levels of 5-FU and inhibition of thymidylate synthase. Tochigi Colorectal Cancer Study Group]. 151 26

Mechanism of synergism and clinical results of methotrexate and 5-fluorouracil (MTX/5-FU) combination therapy for gastric cancer were studied. The response rate against poorly differentiated gastric cancers was 35% in this treatment. This treatment also showed a remarkable effect against cases with pleural and abdominal effusion caused by cancerous disseminations. A promising result was obtained by this treatment as neoadjuvant and postoperative chemotherapy against Borrmann type 4 gastric cancer. A greater dependence on the de novo pathway of pyrimidine synthesis against poorly differentiated gastric carcinoma, which was estimated by the fact that the thymidylate synthetase/thymidine kinase ratio was significantly higher in poorly differentiated gastric cancer than in well differentiated cancer, may potentiate therapeutic results of this treatment.
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PMID:[Mechanism of synergism and clinical results of sequential methotrexate and 5-fluorouracil in the treatment of gastric cancer]. 162 50

Leucovorin (LV), given intravenously the orally becomes 5, 10-methylene tetrahydrofolate in both cancer and normal cells. FdUMP which is an active metabolite of 5-FU binds tightly to thymidylate synthase in the presence of the cofactor 5, 10-methylene tetrahydrofolate. This interaction leads to potentiate the cytotoxic effect of 5-FU by prolonged inhibition of thymidylate synthase. Clinically, the combination of LV and 5-FU is given parenterally by two schedules; 5 consecutive days schedule and weekly schedule. Five 5 consecutive days-schedule is divided into 2 methods. One is a 200 mg/m2/day of LV by Machover, and the other is 20 mg/m2/day of LV by O'Connell. The weekly schedule is a 2-hour infusion of dl-LV (500 mg/m2) and iv bolus of 5-FU (600 mg/m2), given 1 hour after the beginning of LV infusion by Petrelli. A multicenter cooperative study in Japan was conducted to evaluate the clinical efficacy of LV and 5-FU using the weekly schedule by Petrelli. Response rates were 31.5% and 41.2% against advanced gastric and colorectal cancer respectively. Then, we carried out a randomized early phase II study using 250 mg/m2 of l-LV weekly (similar to the schedule of Petrelli's, armA) and 100 mg/m2 (similar to the schedule of Machover's, arm B) or 10 mg/m2 (similar to the schedule of O'Connell's, arm C) of l-LV for 5 consecutive days against gastric cancer. The response rate was 33.3% in arm A, 24.1% in arm B and no response in arm C. Toxicity was within acceptable limits, Toxic effects included diarrhea, stomatitis, anorexia and myelohypoplasia. Our data suggests that high-dose LV and 5-FU seems to be a very promising combination but, there was no responder using low dose (10 mg/m2) of l-LV schedule against gastric cancer patients.
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PMID:[High-dose leucovorin and 5-FU]. 162 51

In recent years the concept of metabolic modulation of fluoropyrimidines by leucovorin has been introduced clinically in patients with advanced colorectal cancer, breast cancer, gastric cancer and head and neck cancer among others. The concept of metabolic modulation was developed in the laboratory and employed clinically. Leucovorin is a noncytotoxic compound used to increase the therapeutic efficacy of 5-fluorouracil. Following 5-fluorouracil activation to 5-fluorodeoxyuridine monophosphates, its binding to thymidylate synthase is stabilized by the active cofactor, 5,10 methylene tetrahydrofolate and its polyglutamate forms. Under these conditions, both the extent and duration of inhibition of thymidylate synthase and consequently, DNA synthesis are more pronounced. The results of clinical trials (phase II and III) indicate that the response rates to 5-fluorouracil/leucovorin modulation are significantly higher than that of fluorouridine alone.
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PMID:Modulation of fluoropyrimidines by leucovorin: rationale and status. 183 38

The effects of preoperative treatment by continuous intravenous infusion of Tegafur, the antagonist of DNA synthesis, were histopathologically studied in 34 patients with gastric cancer. Histologically the treatment was found to be effective in 41.2% of patients with cancer invasion in the mucosa, 58.8% in the submucosa, 61.3% in the muscularis propria, 59.3% in the subserosa and 86.9% of those with metastatic lymph nodes. The treatment was effective, when assessed in terms of the histological type of cancer, in 90.9% of cancers of the differentiated type (papillary adenocarcinoma, well differentiated tubular adenocarcinoma and moderately differentiated tubular adenocarcinoma) and 47.8% of those of the poorly differentiated type (poorly differentiated adenocarcinoma, mucinous adenocarcinoma and signet-ring cell carcinoma), showing a higher rate of efficacy in the differentiated type cancers. Meanwhile, even among patients with cancer of poorly differentiated type, a high efficacy rate (90.0%) was found in those with metastatic cancer of the lymph nodes. No relationship was found between the total doses of Tegafur and histological effects. There was a tendency, however, for a higher frequency of a good response in patients administered more than 4,000 mg of Tegafur. In the patients with a histologically positive effect, 5-FU concentration in the tumor tissue was higher than 0.071 microgram/g. However, some patients showed no response despite a high concentration. This finding suggested that sensitivity to 5-FU and 5-FU metabolism vary depending on the tumor. The inhibitory effect of Tegafur on DNA synthesis is produced through inhibition of thymidylate synthase (TS) by the Tegafur metabolite FdUMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Histopathological studies on antitumor effect of tegafur administered by continuous intravenous infusion]. 211 40

The authors examined the relationship between the level of thymidylate synthase (TS) and the sensitivity to 5-fluorouracil (5-FU) and UFT, a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil in a molar ratio of 1:4. For the studies we used the subrenal capsule (SRC) assay and 15 human gastric cancer tissues. The TS levels were assayed by the ligand-binding technique, using [6-3H]FdUMP. The relative variation of tumor size (delta TuS/TuS0) was calculated to be as follows: delta TuS/TuS0 = [(TuS6 - TuS0)/TuS0] x 100 (%), where TuS6 was the tumor size on day 6 and TuS0 on day 0. The chemosensitivity was considered to be positive when delta TuS/TuS0 in the treated group decreased to below -10%. Decrease in tumor size was marked in case of exposure to UFT (-19.8 +/- 13.0%) (mean +/- standard deviation), compared with that to 5-FU (-9.0 +/- 7.2%), with a statistically significant difference (P less than 0.001). The TS level varied from 1.7 to 30.8 pmol/g gastric cancer tissue and the mean was 7.1 +/- 7.2 pmol/g tissue. A correlation was noted between the TS level and decrease in size of the tumor exposed to 5-FU (r = -0.671) or UFT (r = -0.758): gastric cancer tissue with higher level of TS is more sensitive to 5-FU and UFT than is that with a lower TS level. These findings show that the sensitivity to 5-FU and UFT of gastric cancer tissue is related to the TS level and that UFT shows promise for the treatment of patients with gastric cancer.
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PMID:5-Fluorouracil and UFT-sensitive gastric carcinoma has a high level of thymidylate synthase. 249 66

The biochemical rationale for the potentiation of the effects of 5-FU by MTX is based on an increased PRPP level or MTX polyglutamate produced by MTX. The cytotoxic action of MTX results not only from inhibition of DHFR but also depends upon thymidylate synthetase (TS), a key enzyme in DNA synthesis. We obtained a monoclonal antibody to TS using a hydrophilic peptide consisting of 20 amino acids in the TS amino acid sequence and demonstrated by PAP that TS was detectable in poorly differentiated adenocarcinoma cells but not in well differentiated adenocarcinoma cells. Upon clinical application of sequential doses of MTX and 5-FU, the median survival durations were 318 days and 156 days for scirrhous-type gastric cancer patients and non-scirrhous-type gastric cancer patients respectively. These results suggest that immunohistochemistry with TS antibody is available as an indicator of the effect of this drug regimen.
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PMID:[The role of thymidylate synthetase in sequential dose of MTX and 5-FU in the advanced scirrhous type gastric cancer]. 283 88

Surgical resection of solid tumors was undertaken five to six hours after the oral administration of UFT (300-500 mg/body) in five patients, who were (then) assayed for 5-fluorodeoxyuridylate (FdUMP), total dTMP synthase (TS) and non-FdUMP-bound, free enzyme. Three patients had gastric cancer, and two had mammary cancer. Control solid tumors were obtained without, the drug in eight patients. Six patients had gastric cancer. Eight had mammary cancer. Total TS averaged 2.04 p mol/g in the malignant tissues. TS inhibition averaged 40.1% to 57.1% in gastric cancer and 17.1% to 52.7% in mammary cancer. These data suggest that TS inhibition after oral administration of 5FU derivatives may be usefully studied for biochemical parameters of mechanisms of drug resistance.
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PMID:[Thymidylate synthase inhibition in malignant tumors after oral administration of UFT]. 309 31

In order to estimate tumor chemosensitivity of fluoropyrimidine derivative, inhibition of thymidylate synthetase (TS) was investigated using a nude mouse experimental system. Four human tumors xenografted in nude mice; H-111, SH-8 and SH-10, each established from gastric cancer, and EH-1 from esophageal cancer, were used. When the transplanted tumor volumes reached to approximately 200 mm3, 1-hexylcarbamoyl-5-fluorouracil (HCFU) was given for 5 days. Tumors was removed for the measurement of total and free TS at 0 hr, 6 hrs and 24 hrs after the last administrations. Simultaneously, the anti-proliferative effects were investigated according to the therapeutic protocol of NCI. No positive correlation between the inhibition rate of TS and the anti-proliferative effects was observed, although the absolute values of free TS were similar to the tumor inhibition rates. The measurement of total TS provided a highest concentration in SH-8, while extremely low in EH-1. On the analysis of free TS, a significant increase of the concentration was observed at 24 hrs after the last administration compared with at 6 hrs in SH-8. These results indicate that free TS had a potentiality as a new parameter for predicting tumor chemosensitivity of fluoropyrimidine derivative and the analysis of TS should be affected strongly by the characteristics of enzymic activity of examined tumor.
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PMID:[Inhibition of thymidylate synthetase and antiproliferative effect by 1-hexylcarbamoyl-5-fluorouracil]. 319 Feb 49


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