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*

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*

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

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

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

PURPOSE: Thymidylate synthase (TS) is an important target for chemotherapeutic drugs such as 5-fluorouracil (5-FU). Overexpression of TS has been linked to chemotherapy resistance, but their relationship was not completely understood. We compared the expression level of TS with resistance of colon and gastric cancer cell lines to 5-FU. METHODS: Expression of TS mRNA was determined by RT-PCR assay in 9 colon and 10 gastric cancer cell lines. Cytotoxicity of 5-FU was determined by MTT assay. Apoptosis was determined using propidium iodide staining by flow cytometry. RESULTS: All cancer cell lines tested showed differential levels of TS mRNA expression. Colon cancer cell Colo320 (the highest expression of TS) was more resistant to 5-FU than SNU-C1 (the lowest expression of TS) was. Flow cytometry also showed that 5-FU induced apoptosis less in Colo320 than SNU-C1. But in gastric cancer cells SNU-1 (the highest expression of TS) was not resistant to 5-FU than SNU-16 (the lowest expression of TS) was. CONCLUSIONS: The high level of expression of TS was correlated with resistance of colon cancer cells to 5-FU, but not in gastric cancer cells. Thus, TS may be differently involved in the resistance of gastric and colon cancer cells to 5-FU, which may depend on the origin of cancer cells and status of apoptosis related genes.
Apoptosis ; Cell Line ; Colon* ; Colonic Neoplasms ; Drug Therapy ; Flow Cytometry ; Fluorouracil* ; Propidium ; RNA, Messenger* ; Stomach Neoplasms* ; Thymidylate Synthase

PURPOSE: Thymidylate synthase (TS) is the target enzyme for 5-fluorouracil (5-FU). It is known that TS is related to response, and resistance, following chemotherapy due to colorectal cancer. The object of this study was to identify the clinical significance of TS as a prognostic factor, and its influence on 5-FU based chemotherapy in colorectal cancer. METHODS: We performed a retrospective study on 105 consecutive patients who were operated on, at the Department of Surgery, Korea University, College of Medicine, for colorectal cancer between Jan. 1994 and Dec. 1995. We used formalin fixed, paraffin embedded tissues of resected specimens for our study. For the semi-quantitative study, the specific monoclonal antibody, TS106, was used for immunohistochemical staining. Interpretation of the immunohistochemical staining, for intratumoral TS expression, was divided into 4 grades: intensity 0, 1 , 2 , 3 were defined as, a total absence of TS immuno staining, less than 25%, 25~50% and more than 50%, of tumor staining positive, respectively. Grades 0, 1 , and 2 were regarded as low TS expression groups and 3 regarded as a high TS expression group. We then analyzed 5-year survival rates, according to Dukes' stage, and whether systemic chemotherapy was performed, or not, according to TS expression. RESULTS: Of the 105 patients, 91 (86.7%) showed TS expression, 21 (20%) with high TS expression and 84 (80%) were low TS expression. As Dukes' stage advanced, the incidence of high expression of TS increased (P=0.048). In Dukes' stage B2, 5-year survival rates for the low TS expressed group was better than for the high TS expressed group (P=0.0052). In patients who received postoperative chemotherapy, 5-year survival rates for the low TS expressed group were better than for the high TS expressed group (P=0.049). CONCLUSION: These data suggest the expression of intratumoral TS, studied by immunohistochemical staining, is relevant to the prognosis of colorectal cancer, especially Dukes' stage B2. It is also related to the response rate of 5-FU based systemic chemotherapy in colorectal cancer.
Colorectal Neoplasms* ; Drug Therapy ; Fluorouracil ; Formaldehyde ; Humans ; Incidence ; Korea ; Paraffin ; Prognosis ; Retrospective Studies ; Survival Rate ; Thymidylate Synthase*

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