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)

We report herein a rare case with advanced gastric cancer combined with group 4 lymph node and lung metastases that responded remarkably to neoadjuvant chemotherapy. A 65-year-old man was found to have a well-differentiated type 3 gastric cancer that invaded the duodenum locally and was accompanied with Virchow's, para-aortic lymph nodes, and multiple lung metastases based on physical, endoscopic, and radiological examinations. In addition, his carbohydrate antigen (CA) 19-9 was elevated to 3965U/ml, and CA72-4 to 46U/ml. Prior to surgery, he was treated with 5-fluorouracil (5-FU; 500mg/body per day) and low-dose cisplatinum (CDDP; 10mg/body per day) as neoadjuvant chemotherapy for 6 weeks. As a result, a partial response was obtained in all lesions, and CA19-9 and CA72-4 decreased to 463U/ml and 9.4U/ml, respectively. Four weeks after the completion of neoadjuvant chemotherapy, a distal gastrectomy was performed, and a histopathological examination of the resected specimen showed a grade 2 response to chemotherapy. Immunohistochemically, the thymidylate synthase expression level was very low in the tumor tissues, which might account for the good response to the combination chemotherapy with 5-FU and CDDP observed in the present case.
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PMID:Gastric cancer with Virchow's and multiple lung metastases showing a remarkable response to preoperative chemotherapy: report of a case. 1132 46

We studied apoptosis and thymidylate synthase (TS) inductions by 5-fluorouracil (5-FU) in gastric cancer cells with wild-type p53 (MKN-45 and MKN-74) and with mutated p53 (MKN-28 and KATO-III). Apoptotic inductions in MKN-45 and MKN-74 were stronger than those in MKN-28 and KATO-III, suggesting that wild-type p53 may contribute to the induction of apoptosis. After continuous exposure to 0.1 microg/ml of 5-FU for 96 h, no TS induction was obtained in KATO-III, while approximately twice the amount of TS was observed compared to non-treatment cells in MKN-45, MKN-74, and MKN-28. The results of immunohistochemical staining for TS and p53 showed no relation between these two protein expressions in endoscopic biopsy specimens of 25 patients with advanced gastric cancer. These results indicated that p53 status may not play a pivotal role in regulating TS expression. We found no significantly different effects of 5-FU between intermittent (repeat of 24-h continuous infusion and 24-h drug-free) and continuous treatments in either MKN-28 or stem cells (CD34+ hematopoietic progenitor cells) when the same area under the time-concentration curve of 5-FU was administered. The TS induction in MKN-28 cells by intermittent treatment was significantly higher than that by continuous treatment; however, most TSs in both types of 5-FU treatment cells were of the inactive form, i.e., TS bound to FdUMP, a 5-FU metabolite. Therefore, neither intermittent nor continuous treatment appears to induce 5-FU resistance related to the level of increment free TS. In conclusion, our observations suggested that p53 mutation may be associated with apoptotic induction by 5-FU; however, p53 status may not strongly affect TS induction by 5-FU. Intermittent treatment can be replaced with continuous treatment without causing 5-FU resistance.
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PMID:Apoptosis and thymidylate synthase inductions by 5-fluorouracil in gastric cancer cells with or without p53 mutation. 1144 54

The patient was a 65-year-old woman with type 3 gastric cancer (por) in the upper third of the stomach invading esophagus. Because of No. 16 lymph node swelling on abdominal CT examination, she was treated with FLP (5-fluorouracil + Leucovorin + cisplatin) as a neoadjuvant chemotherapy (NAC). The activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in the primary tumors upon endoscopic examination were 2.72 pmol/g tissue and 129.1 pmol/mg/min, respectively. After the second course, we carried out lower esophagectomy and spleno-total gastrectomy with D3 including the No. 16 lymph nodes. Histopathological examination of resected specimens showed dense fibrosis and xanthogranulomatous inflammation with foamy cells and giant cells. No residual carcinoma was seen (complete response). The patient is still alive with no sign of recurrence 1 year after surgery. NAC by combination of FLP is thought to be effective for the treatment of highly advanced gastric cancer, especially in cases with locally advanced disease and lymph node metastasis such as the present. Although no relations were seen between NAC effects and TS, DPD activities and TSIR in primary tumors in 12 gastric cancer patients, the survival rate of a low DPD activity group was significantly better than a high group in 106 cases undergoing adjuvant chemotherapy including 5-FU after surgery.
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PMID:[A complete response after neoadjuvant chemotherapy for advanced gastric cancer with esophageal invasion]. 1181 67

BACKGROUND: The immunohistochemical expression of thymidylate synthase (TS) and thymidine phosphorylase (TP) was examined in a comparative study of the recurrence rates and prognoses of patients with advanced gastric cancer at the same stage.METHODS: We examined the resected specimens of 67 patients with stage IIIB gastric cancer (pT3, pN2, M0) under 70 years of age who had undergone curative gastrectomy followed by adjuvant chemotherapy with 5-fluoropyrimidines. Paraffin sections of the resected specimens were stained with human anti-TS polyclonal and anti-TP monoclonal antibodies by the avidin-biotin-peroxidase complex (ABC) method.RESULTS: The overall expression of TS and TP was 45.4% and 43.4%, respectively. The postoperative survival curve for the TS-positive group was significantly depressed compared with that for the TS-negative group ( P = 0.0480). The survival curves for TP-positive and TP-negative groups did not show any difference. In regard to the combination of TS and TP expression, the best survival curve was obtained for the TS(-)/TP(+) group, followed by those for the TS(-)/TP(-), TS(+)/TP(-), and TS(+)/TP(+) groups in descending order. With regard to the recurrence site, there was no significant difference in peritoneal recurrence in relation to positivity for TS or TP. Lymph node recurrence, however, was significantly higher in the TS-positive and TP-positive groups, with P-values being 0.0466 and 0.0058, respectively, versus the corresponding negative groups. The incidence of hepatic recurrence was higher in the TP-positive group than in the TP-negative group ( P = 0.0910). As for the total doses of 5-fluoropyrimidines given, more favorable survival curves were obtained for the high dose of negative TS and TP groups, but no significant differences were observed in their positivities.CONCLUSION: The expressions of TS and TP showed different characteristics in overall survival and recurrence rate or site. They should be used for predicting prognosis in comprehension on their properties.
Gastric Cancer 1999 Nov
PMID:Expression of thymidylate synthase and thymidine phosphorylase in recurrence and survival rates of advanced gastric cancer. 1195 91

Thymidylate synthase (EC 2.1.1.45) and thymidine kinase (EC 2.71.21) are key enzymes involved in de novo and salvage pathways for pyrimidine nucleotide synthesis. Both enzyme activities are increased in rapidly proliferating normal, fetal and neoplastic tissues. In a previous study, the activities of thymidylate synthase and thymidine kinase were relatively predominant in the poorly-and well-differentiated types of a gastric cancer. In the present study of patients with colorectal cancer, the serum thymidine kinase activities are elevated in cases at a clinically late stage, and in cases with a recurrence and a distant metastasis associated with abundant blood supply, i.e. metastasis to the liver, lung and bone. Well-differentiated colorectal cancer shows higher thymidine kinase activity than moderately-well-differentiated type as was previously shown in gastric cancer patients. Furthermore, neoadjuvant chemotherapy using the 5-fluorouracil derivative UFT demonstrates a stronger suppression of increased activities of thymidylate synthase in the tumorous tissues than in the non-tumorous mucosa.
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PMID:Human colorectal malignancy and oral UFT. 1201 14

Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.
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PMID:Expression of multidrug resistance-associated protein1,P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. 1208 7

We used real-time reverse-transcription polymerase chain reaction (RT-PCR) to assay expression of the mRNA of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in gastric cancer tissue with the objective of establishing a system to measure TS and DPD in ultra-low-volume samples. Nude mouse xenografts of 5 human gastric cancer cell lines and 85 clinical samples were used as the specimens in this study. Sensitivity to 5-fluorouracil (5-FU) was determined on the basis of the relative tumor proliferation rate in mice and the results of ATP assay using serum-free cultures of the clinical samples. mRNA expression was measured in tumor tissue by real-time RT-PCR using the ABI PRISM 7700 system. The values for expression of the mRNA for TS and DPD were corrected according to the level of glyceraldehyde-3-phosphate dehydrogenase mRNA expression. The xenografts yielded correlations between TS and DPD mRNA expression and the activity of the enzymes (TS: rs=0.700, DPD: rs=0.900), and an inverse correlation was noted between the mRNA levels and sensitivity to 5-FU (TS: rs=-0.900, DPD: rs=-0.800). The clinical samples showed an inverse correlation between 5-FU sensitivity and mRNA expression (TS: rs=-0.518, DPD: rs=-0.564). Sensitivity to 5-FU was noted only in cases in which TS mRNA expression and DPD mRNA expression were both low. Real-time RT-PCR can provide a highly sensitive assessment of TS and DPD mRNA expression in gastric cancer, and it was useful for predicting 5-FU sensitivity.
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PMID:Quantitative measurement of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level in gastric cancer by real-time RT-PCR. 1249 74

We identified two novel deletion variants of the thymidylate synthase transcript in gastric cell lines. Sequence analyses indicate that none of these variants results in introduction of a premature stop-codon or a frame shifts. In 39 gastric cancer samples, both the full-length and one-deletion variant messages were detected in cancerous as well as non-cancerous tissues. However, another isoform was found in only seven of 39 cancerous tissues. Our results provide important information to assist more detailed studies on the regulation of thymidylate synthase activity.
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PMID:Differential alternative splicing expressions of thymidylate synthase isoforms. 1270 68

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

The predictive values of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) gene expressions were retrospectively evaluated in patients with gastric cancer treated by a regimen containing S-1. The study population consisted of 53 patients registered into different two phase II studies for metastatic gastric cancer; 27 patients treated by S-1-alone study: 26 patients treated with S-1 combined with irinotecan (CPT-11). TS and DPD gene expressions in primary tumours were measured by the real-time reverse transcription PCR method. There was no statistical difference in DPD gene expression in terms of response in cases treated with S-1 alone and those treated with S-1 plus CPT-11. TS mRNA of responding tumours was lower than that of nonresponding ones when treated with S-1 (P<0.005). In the S-1-alone group, taking TS cutoff as the median values, the response rate in the low TS group was 50%, but only 8% in the high TS group (P<0.05). Patients with low TS gene expression survived longer than those with high TS gene expression (P<0.0001). However, there was no statistically significant difference in response rate and survival between patients with low TS tumours and those with high TS tumours, when the cutoff was taken as the median value of TS gene expression in the group treated with S-1 plus CPT-11. In conclusion, treatment effects of S-1 monotherapy for gastric cancer were determined by the status of TS gene expression, regardless of DPD gene expression. TS predictive power was overcome by CPT-11 combination therapy with S-1.
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PMID:Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer. 1535 15


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