No abstract available
Fluorouracil* ; Lovastatin* ; Stomach Neoplasms* ; Stomach* ; Thymidylate Synthase

No abstract available.
Prognosis* ; Stomach Neoplasms* ; Stomach* ; Thymidylate Synthase*

PURPOSE: 5-fluorouracil is one of the widely used chemotherapeutic agent whose metabolic product forms tight covalent binding complex with thymidylate synthase (TS) and thereby blocks the DNA synthesis process. Expression of TS has been studied as a mechanism of drug resistance and as a prognostic factor for various cancers. METHODS: The relation between TS expression in surgically resected specimens and clinicopathologic features was examined in 62 patients with gastric cancer. Immuno histochemical demonstration of the protein was achieved using an anti-TS monoclonal antibody. RESULTS: In Lauren's classification, TS expressions of the intestinal type and the diffuse type were 21.93% and 14.96% respectively (P=0.02). And TS expression in a group with lymphatic invasion was higher (26.15%) than that in a group without lymphatic invasion (16.15%)(P=0.0001). There were no significant differences between the TS expressions associated with other clinicopathologic features (P>0.05). CONCLUSION: For the purpose of assessing the applicability of TS expression as a prognostic factor and as a mechanism for drug resistance, assessment of TS expression must be standardized. Although direct correlations between TS expression and other clinicopathologic features were found only in Lauren's classification and lymphatic invasion, further investigations of the relation between TS expression and drug resistance of 5-FU must be continued to provide data for choosing chemotherapuetic agents for use in patients with gastric cancer.
Classification ; DNA ; Drug Resistance ; Fluorouracil ; Humans ; Stomach Neoplasms* ; Thymidylate Synthase*

PURPOSE: The purpose of this study is to suggest a probable problem in chemosensitivity tests performed in practice and to speculate on practicable measures for more accurate chemosensitivity evaluation. METHODS: Three colorectal cancer cells (RSC, RRC1, and RRC2) were treated with 5-fluorouracil (5-FU). Inhibition percentage (%inhibition) of cancer cells and relative quantitation of thymidylate synthase (TS) mRNA were measured on day 2, day 5 after replacement of 70% media on day 2, day 7, and day 3 after replacement of all media on day 7. Doses that produced 50% inhibition (Dm) were calculated to evaluate drug effect. Relative quantitation of TS mRNA and correlations between TS mRNA levels and 5-FU concentrations were analyzed. RESULTS: RRC1 was more resistant than RRC2 on day 7, but Dm value of RRC2 increased three days after replacement of media from 12.3 to 18.1. Mean TS mRNA levels of RSC on D2 and D7 were significantly lower than those of RRC1 and RRC2, respectively (P = 0.004, P = 0.004 on D2; P = 0.010, P = 0.006 on D7). TS mRNA levels in RRC1 were significantly reversely correlated with 5-FU concentrations on day 2 (correlation coefficient = -0.867, P = 0.015). On the other hand, correlations were not significant in RRC2 (r = 0.067). CONCLUSION: Evaluating %inhibition of cancer cells at one point in chemosensitivity tests seems to be inadequate in determining chemotherapeutic regimens. Multilateral approaches, such as trials evaluating cancer cell survival before and after media replacement and correlations between TS mRNA levels and 5-FU concentrations, needs to be implemented for the practical application of chemosensitivity tests.
Cell Line ; Cell Survival ; Colorectal Neoplasms ; Fluorouracil ; Hand ; RNA, Messenger ; Thymidylate Synthase

BACKGROUND: Pemetrexed, a multi-targeted antifolate has been used as a second line treatment against non-small cell lung cancer (NSCLC). We aimed to clarify the efficacy and survival according to line of treatment, histologic type, and expression of thymidylate synthase (TS). METHODS: Ninety-eight patients were treated with pemetrexed as a second line treatment (n=43) or as an additional course of treatment (n=55). TS expression was studied with immunohistochemistry and graded as 0 to 3 based on the extent of expression. RESULTS: The response rate (RR) in 98 subjects was 10.2% and the disease control rate (DCR=PR+SD) was 30.6%. RR and DCR were 12.7% and 32.7% in non-squamous cell carcinoma (NSQC) compared to 7.0% and 27.9% in squamous cell carcinoma (SQC) (p>.05). No significant differences in RR and DCR were observed between a second line group (4.7%, 20.9%) and a further line group (14.5%, 38.2%). A similar trend was observed in the 88 response evaluable subjects. TS was expressed in 28.6% (grade 1), 24.5% (grade 2) and 7.1% (grade 3), respectively, and it was not expressed in 39.8% of subjects. TS expression rate was significantly higher in the SQC (72.1%) compared to NSQC (50.9%, p=0.033). However, the efficacy of pemetrexed was not significantly different by the extent of TS expression. CONCLUSION: Pemetrexed showed efficacy, not only in a second-line setting, but also in further lines of treatment for NSCLC. The efficacy of pemetrexed tended to be higher in patients with NSQC compared to SQC. TS expression rate was significantly higher in SQC compared to NSQC.
Carcinoma, Non-Small-Cell Lung ; Carcinoma, Squamous Cell ; Glutamates ; Guanine ; Humans ; Immunohistochemistry ; Thymidylate Synthase ; Pemetrexed

BACKGROUND: The expressions of thymidylate synthase (TS), E2F-1, pRb, and p53 are correlated with DNA synthesis. The significance of their expressions is still controversial for predicting the outcome of 5-fluorouracil (5-FU) therapy in the patients with advanced gastric carcinoma. Furthermore, their prognostic value in the metastatic lesions of gastric carcinoma has not yet been confirmed. METHODS: To ascertain their prognostic value, we immunohistochemically analyzed the expressions of TS, E2F-1, pRb, and p53 in the primary tumors and the related metastatic lymph nodes, and we then compared the survival between the high and low expression group of each protein. Ninety four patients with advanced gastric carcinoma who were treated by complete resection and adjuvant 5-FU chemotherapy were analyzed. RESULTS: The TS expression in primary tumors was significantly correlated with that of E2F-1. The expression of these genes showed no significant difference between the primary tumors and the metastatic lymph nodes except for E2F-1, which was significantly higher in the lymph node metastasis than in the primary tumors. After complete resection and 5-FU-based adjuvant chemotherapy, patients with a high TS expression in the primary tumors showed a longer survival than those patients having primary tumors with a low TS expression (p=0.0392). CONCLUSION: A high TS expression in the primary tumors may be related to a better outcome for advanced gastric cancer patients who were treated with 5-FU chemotherapy after curative resection.
Chemotherapy, Adjuvant ; DNA ; Drug Therapy* ; Fluorouracil* ; Humans ; Lymph Nodes ; Neoplasm Metastasis ; Stomach Neoplasms* ; Thymidylate Synthase*

OBJECTIVE: To evaluate the expression of thymidylate synthase (TS) in myoepithelial cells (MECs) of salivary adenoid tissues and explore its clinical significance. METHODS: Immunohistochemical staining EnVision method was used to detect the expression of TS, P63, Calponin, CK5/6 and S-100 in 32 salivary gland specimens, including 10 non-neoplastic and salivary inflammation specimens, 11 mixed tumor specimens, 5 basal cell carcinoma specimens and 6 adenoid cyst carcinoma specimens. The specificity and sensitivity of TS as a specific molecular marker of salivary muscle epithelial cells were evaluated in comparison with P63, Calponin, CK5/6 and S-100. RESULTS: The expression pattern of TS in all the salivary gland tissue specimens was identical with that of p63. TS and P63 both showed strong immunohistochemical expressions in MECs of salivary adenoid tissue specimens. Calponin, CK5/6, and S-100 showed cytoplasmic/membranous expressions in the MECs. In addition, TS exhibited weak or moderate cytoplasmic expression in a few salivary gland epithelial cells, cancer cells and scattered stromal cells, with negative expression in the cell nuclei. The expression of TS in the MECs of all the salivary adenoid specimens was highly consistent with those of P63, Calponin, CK5/6 and S-100 (>0.05) Except for CK5/6 expression in Salivary inflammation and Salivary gland specimens. Kappa>0.75. The specificity and sensitivity of TS as a molecular marker of MECs were both 100%. CONCLUSIONS TS is a new specific marker of MECs for differential diagnosis of salivary gland tumors.
Adenoids ; Biomarkers, Tumor ; Carcinoma, Adenoid Cystic ; Epithelial Cells ; Humans ; Salivary Gland Neoplasms ; Thymidylate Synthase

OBJECTIVE: Gastric carcinoma is one of the most common cause of death in Korea with limited effectiveness of chemotherapy. Thymidylate synthase(TS) is a critical therapeutic target for the fluoropyrimidine cytotoxic drugs, that are the mainstay of the treatment for the advanced gastrointestinal malignancies. We assessed the relationship between the levels of TS expression and survival and effect of 5-fluorouracil based chemotherapy in gastric adenocarcinoma. METHODS: Thirty six patients with gastric adenocarcinoma who underwent curative resection of stomach at Ewha Womans University Hospital were evaluated. TS protein expression in tumor tissues was assessed by standard immunohistochemical staining techniques with TS 106 monoclonal antibody. RESULTS: TS expression was high(3+) in 19 patients (52.8%) and low(< or =2+) in 17 patients(47.2%). Between these two groups, there was no significant difference in the histopathologic type or stage. Seventy-two point five percent of patients with low TS expression were disease free at 5 years compared with 58.2% of patients with high TS expression(p=0.31) and 73.7% of patients with low TS expression were alive at 5 years compared with 61.4% of patients with high TS expression(p=0.34). In patients with high TS expression, disease-free survival (DFS) and overall survival(OS) of patients who received adjuvant chemotherapy were longer than those of patients with surgery alone without significance(p=0.28, p=0.16). CONCLUSIONS: We could not confirm the association between the level of TS expression in tumor tissues and DFS and OS of patients with gastric adenocarcinoma who underwent curative resection. Further study with more cases as well as prospective study will be necessary for establishment of relationship between TS expression of tumor and prognosis of gastric adenocarcinoma
Adenocarcinoma* ; Cause of Death ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Drug Therapy ; Female ; Fluorouracil ; Humans ; Korea ; Prognosis* ; Stomach ; Thymidylate Synthase*

PURPOSE: In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5-FU-based chemotherapy is still important, as those unlikely to benefit could be spared the harmful side effects. The expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and p53 have been known to be associated with the clinical response to 5-FU-based therapy as well as the prognosis, and that of vascular endothelial growth factor (VEGF) is associated with poor survival. MATERIALS AND METHODS: The relationship between the expressions of TS, TP, VEGF and p53 in primary tumors, using immunohistochemistry, and the response of 45 metastatic colorectal cancer patients (M: F=25: 20, median age 59 yrs) to 5-FU-based chemotherapy were evaluated. RESULTS: Thirty-seven patients were treated with 5-FU/ LV/irinotecan (FOLFIRI) and 8 with 5-FU/LV/oxaplatin (FOLFOX). The overall response rate was 28.9% (13/45). When immunohistochemically analyzed with monoclonal antibodies against TS, TP, VEGF and p53, 55.6% of the patients (25/45) were positive for TS, 48.9% (22/45) for TP, 82.2% (37/45) for VEGF, and 80% (36/45) for p53. There was a significant difference in the intensity of TS expression between the clinical responders and non-responders (p=0.036). In terms of the staining pattern of TS expression, diffuse staining was correlated with a poor response (p=0.012) and poor survival (p=0.045). However, there was no correlation between the expressions of TP, VEGF or P53 and the response to chemotherapy. CONCLUSION: These results suggest that the expression of TS in primary colorectal cancer might be an important prognostic factor for chemotherapy response and survival, and might be a useful therapeutic marker for the response of chemotherapy.
Antibodies, Monoclonal ; Colorectal Neoplasms* ; Drug Therapy* ; Fluorouracil ; Humans ; Immunohistochemistry ; Prognosis ; Thymidine Phosphorylase* ; Thymidine* ; Thymidylate Synthase* ; Vascular Endothelial Growth Factor A*

PURPOSE: The genetic polymorphism and intracellular activity of methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) is clinically associated with carcinogenesis and biological therapeutic effect in gastrointestinal malignancies. We aimed to elucidate the susceptibility of gastric cancer according to MTHFR and TS gene polymorphism. METHODS: This study was designed as a hospital-based case-control study in a single institute. The gastric cancer group (n=300) for the study was diagnosed at first time as tubular adenocarcinoma, and the control group (n=100) was diagnosed as no malignancy in the endoscopic biopsy. The genetic polymorphism of TS and MTHFR were confirmed by PCR. RESULTS: The MTHFR mutant type had a more than 2-fold increased risk of developing gastric cancer (RR: 2.341). But, only heterozygote type (677CT) revealed significantly higher susceptibility compared to wild type (RR: 2.581). In TS gene genotype, the mutant genotype rate (2R/3R and 3R/3R) was significantly higher in gastric cancer group compared to control group (P=0.008), and the mutant type had a more than 3-fold increased risk of developing gastric cancer (RR: 3.222). In combined MTHFR and TS, 677CT+2R/3R and 677CT+3R/3R there was more than a 3-fold increased risk rate of developing gastric cancer compared with other combinations (RR, 3.474 in 677CT with 2R/3R; RR, 3.895 in 677CT with 3R/3R). CONCLUSION: This study shows a significant association between the MTHFR and TS polymorphisms and susceptibility to gastric cancer, providing a genetic basis. The polymorphisms study of two genes could be applied as susceptibility markers, clinically, for gastric cancer.
Adenocarcinoma ; Biopsy ; Case-Control Studies ; Genotype ; Heterozygote ; Methylenetetrahydrofolate Reductase (NADPH2) ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Stomach Neoplasms ; Thymidylate Synthase