UMLS:C0024623 - FACTA Search

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Query: UMLS:C0024623 (gastric cancer)
36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The measurement of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) enzymatic activities and mRNA levels in tumors may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in this study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD mRNA levels. We also measured TS and DPD enzymatic activities and mRNA levels in surgically resected gastric cancer samples, as well as in adjacent normal gastric mucosa. TS and DPD activities were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-PCR (RT-PCR) co-amplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. In resected tumor specimens, TS and DPD activities ranged from 7.1 to 176.6 fmol/mg protein and from 3.6 to 99.8 pmol/min/mg protein, respectively, while TS and DPD mRNA levels ranged from 0.50 to 21.12 and from 0.014 to 7:22, respectively. There were no significant correlations between TS/DPD levels and other clinicopathological factors, except for low DPD mRNA levels in undifferentiated carcinoma. Both TS activity and mRNA levels were significantly higher in tumor tissues compared to normal adjacent mucosa. In contrast, there was no significant difference between tumoral and non-tumoral DPD activity, although tumor tissue showed significantly lower DPD mRNA levels than non-tumoral tissue. High tumoral TS mRNA levels in preoperative biopsy specimens from patients with stage III/IV was associated with poor survival outcome after surgery compared with patients with low tumoral TS mRNA levels. In contrast, DPD levels had no influence on prognosis. We conclude that high tumoral TS levels and low tumoral DPD mRNA may indicate the selective cytotoxicity of 5-FU on gastric cancer, and that tumoral TS mRNA levels may be a prognostic factor for patients with stage III/IV gastric cancer.
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PMID:Thymidylate synthetase and dihydropyrimidine dehydrogenase levels in gastric cancer. 1069 32

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and enzymatic activities of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in the study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels. TS and DPD enzyme activity and mRNA levels were also measured in resected tumor tissue samples obtained after surgical resection. TS and DPD activity were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), with co-amplification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. 5-FU sensitivity of resected tumor specimens was measured by the tetrazolium-based colorimetric assay (MTT assay). Both TS and DPD mRNA levels correlated well between biopsied and resected tumor specimens. A statistically significant correlation was also observed between mRNA levels in biopsied specimens and enzymatic activities in resected specimens. DPD levels significantly correlated with 5-FU sensitivity, such that high DPD activity and high DPD mRNA levels resulted in low sensitivity to 5-FU. In contrast, no correlation was observed between TS activity or TS mRNA levels and 5-FU sensitivity. We conclude that tumor DPD mRNA level, as assessed from biopsy specimens obtained by gastrofiberscopy, may be a useful indicator in predicting tumor sensitivity to 5-FU in patients with gastric cancer.
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PMID:Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: possible predictor for sensitivity to 5-fluorouracil. 1074 51

Expression of thymidylate synthase (TS) has been studied as a prognostic factor and mechanism of drug resistance in gastric cancers. The relationship between TS expression in surgically resected specimens and clinicopathological factors was examined in 216 gastric cancer patients. Immunohistochemical demonstration of the protein was achieved using an anti-TS polyclonal antibody. Positive TS staining was observed in 50 patients (23.1%). Lymph node metastasis was more frequent in patients with TS-positive tumors than in those with TS-negative tumors (P<0.01). Patients were followed for more than 5 years and survival was examined. In 163 patients who received fluorouracil (FU)-based chemotherapy, the overall 5-year survival rate was 41.8% for patients with TS-positive tumors and 57.0% for patients with TS-negative tumors (P<0.01). In the 53 patients who did not receive chemotherapy, these figures were 25.6% and 79.5%, respectively (P<0.05). In patients with T3 gastric cancer who were treated with curative gastrectomy, however, FU-based chemotherapy did not affect survival of either patients with TS-positive tumors or with TS-negative tumors. Multivariate analysis also revealed TS expression to be a significant variable for predicting postoperative survival (P<0.05). These results indicate that TS expression can be used as an independent prognostic factor for patients with gastric cancer. However, TS expression is not a major predictor of the efficacy of FU-based chemotherapy.
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PMID:Expression of thymidylate synthase in relation to survival and chemosensitivity in gastric cancer patients. 1096 17

Many reports have demonstrated that thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are biomarkers for the response and prognosis of patients treated with 5-fluorouracil (5-FU)-based chemotherapy. A newly developed orally administered drug, fluoropyrimidine (S-1), has been developed with clinical efficacy when combined with an inhibitor of DPD. In this study, the relationship between immunoreactivity to TS and DPD in biopsy specimens and the effects of chemotherapy was investigated in 41 patients treated with S-1 therapy for advanced gastric cancer. Response rates were 54% (13/24) in TS(+) and 53% (9/17) in TS(-) patients (p=0.938), and those of DPD(+) and (-) patients were 61% (11/18) and 48% (11/23) (p=0.397), respectively. The median survival time of all the subjects was 253 days. There was no significant difference in median survival time between TS(+) patients (284 days) and (-) patients (189 days: p=0.670). The 18 DPD(+) patients had median survival times slightly longer (338 days) than the 23 patients with DPD(-) (207 days: p=0.206). This study indicates that S-1 may be effective in the treatment of gastric cancer patients, regardless of intratumoral TS and DPD immunoreactivity status. Further studies are needed to confirm these results with larger numbers of patients.
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PMID:Clinical implications of immunoreactivity of thymidylate synthase and dihydropyrimidine dehydrogenase in gastric cancer treated with oral fluoropyrimidine (S-1). Study Group of S-1 for Gastric Cancer. 1099 74

We have recently demonstrated that HDFL (high-dose 5-FU 2600 mg m-2 week-1 and leucovorin 500 mg m-2 week-1, weekly 24-h infusion) is highly active in the treatment of gastric cancer. To further clarify the possible mechanism underlying the improved activity of HDFL compared with conventional 5-FU regimens, we conducted in vitro studies examining the effect of these regimens on the differential regulation of thymidylate synthase (TS) in NCI-N87, a human gastric cancer cell line. The expected serum concentrations of 5-FU are 100-200 mM (lasting for less than 30 min) and 5-10 mM (lasting for 24 h) for the conventional 5-FU regimens (bolus injection or short intravenous infusion of 5-FU 370-500 mg m-2) and the HDFL regimens, respectively. Western blot analysis revealed that 24-h exposure of NCI-N87 to 2.5-10.0 mM of 5-FU resulted in a dose-dependent depletion of free TS, lasting for more than 24 h. In contrast, 30-min exposure of NCI-N87 to 200 mM of 5-FU resulted in a less than 12-h depletion of free TS. Moreover, 24-h exposure to 5-FU resulted in a higher S-phase blockade and enhanced cytotoxicity. In both modes of 5-FU treatment, the initial rapid depletion of free TS was accompanied by a rapid increment of a higher-molecular-weight TS molecule, suggesting that rapid formation of the ternary complex was the key mechanism of 5-FU action during this period. Northern blot analysis showed that the steady-state mRNA of TS was not affected by either of the schedules. We conclude that 24-h exposure of gastric cancer cells to low concentration of 5-FU resulted in better suppression of free TS, a higher degree of S-phase blockade, and enhanced cytotoxicity compared to 30-min exposure to high concentration of 5-FU. These in vitro results may help explain the improved clinical efficacy of HDFL regimens compared to conventional 5-FU regimens.
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PMID:Prolonged and enhanced suppression of thymidylate synthase by weekly 24-h infusion of high-dose 5-fluorouracil. 1107 61

Because of the low chemosensitivity of gastric cancer to conventionally available agents, several approaches were investigated to design "order made" treatments using chemosensitivity tests, including the histoculture drug response assay (HDRA) which was useful in evaluating the appropriate cancer chemotherapy for the patients with Stage III/IV gastric cancer. A recent investigation using a molecular biological method was introduced to predict the sensitivity of gastric cancer specimens to 5-fluorouracil (5-FU) by dihydropyrimidine dehydrogenase (DPD) activity and its mRNA. The low activity of DPD and DPD mRNA resulted in the low sensitivity to 5-FU, although thymidylate synthetase activity was not related to the sensitivity to 5-FU. This method is promising, since a small amount of material obtained through gastrofiberscopy will be adequate to assess DPD mRNA to predict the sensitivity to 5-FU. On the other hand, some randomized control trials with a huge cohort have indicated the usefulness of a "docetaxel + cisplatin + 5-FU" regimen for advanced and recurrent gastric cancer, and "5-FU + LV + radiation" as an adjuvant therapy for advanced gastric cancer. Furthermore, the efficacy of adjuvant chemotherapy after curative resection for gastric cancer was warranted by a meta-analysis of 19 published randomized trials. The "order made" and "standard" therapies will be complementary in the further development of chemotherapy against gastric cancer.
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PMID:[Recent advance in gastric cancer chemotherapy]. 1110 35

We evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (> or = 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P = 0.002), poorly differentiated histology (P = 0.015), and mixed type in Lauren's classification (P = 0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs. 57.2%, P = 0.548) and overall survival (59.6% vs. 59.3%, P = 0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary.
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PMID:Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. 1116 74

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