Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is characterized by significant gastrointestinal dysmotility. Early and long-term nutritional therapy is highly recommended. We report a case of MNGIE in a patient who was undergoing long-term nutrition therapy. He was diagnosed with a serious symptom of fatty liver and hyperlipidemia complications, along with homozygous mutation of the thymidine phosphorylase (TYMP) gene (c.217G > A). To our knowledge, this is the first report of such a case. Herein, we describe preventive measures for the aforementioned complications and mitochondrial disease-specific nutritional therapy.
Fatty Liver ; Humans ; Hyperlipidemias ; Nutrition Therapy* ; Thymidine Phosphorylase

OBJECTIVES: Angiogenesis is a critical factor in the progression of solid tumors, including cervical cancer. However, the association between the expression of thymidine phosphorylase(TP) and clinicopathological factors has scarcely been examined in cervical neoplasia. This study was performed to evaluate the level of TP expression in cervical intraepithelial neoplasia(CIN) and invasive cancer respectively, and to observe the relationship between expression of TP and various clinicopathological factors of cervical cancer. PATIENTS AND METHODS: Total 81 cervical biopsy specimens obtained from Jan. 1995 to Aug. 1996 at YUMC were evaluated for the expression of TP : among these, 9 were pathologically confirmed as benign, 6 as CIN I, 11 as CIN II, 12 as CIN III, and 43 as invasive squamous cell carcinoma(SCC) of uterine cervix. These specimens were immunostained to examine the expression of TP and the results of immunostaining were correlated with various clinicopathological factors of cervical cancer. RESULTS: TP expression progressively increased along a continuum from normal epithelium to invasive SCC(p<0.05) and TP expression in cancer cells was well correlated with pelvic lymph node metastasis(p<0.01), large tumor size(p<0.05) and advanced stage(p<0.05). Overall survival rate for 28 patients with TP-positive cervical cancer was significantly lower than that of 15 patients with TP-negative cervical cancer. CONCLUSIONS: With this study, we can speculate that TP might play a role in the growth and metastatic process of cervical neoplasia and be a possible prognostic factor of cervical cancer.
Biopsy ; Cervix Uteri ; Epithelium ; Female ; Humans ; Lymph Nodes ; Survival Rate ; Thymidine Phosphorylase* ; Thymidine* ; Uterine Cervical Neoplasms

OBJECTIVE: We evaluated the relationship between the expression of Ki-67 and thymidine-phosphorylase (TP) according to the cancerous progression of uterine cervical cancer with immunohistochemical method. METHODS: The material was obtained from hysterectomized uterus and punched cervical specimen for two years from 1998 to 1999 at the Soonchunhyang Chunan hospital. The material included 15 normal epithelium, 13 CIN I/II, 21 CIN III, 15 microinvasive carcinoma and 13 invasive carcinoma. Monoclonal antibodies of Ki-67 and TP were used for immunohistochemical determination of cellular proliferation and angiogenic activity. RESULTS: 1. The positive rate of thymidine phosphorylase in each group of normal epithelium, CIN I/II, CIN III, microinvasive carcinoma and invasive carcinoma were 6.7%, 23.1%, 38.0%, 73.3%, 84.6% respectively. 2. The labeling indexes of Ki-67 in each group of normal epithelium. CIN I/II, CIN III, microinvasive carcinoma and invasive carcinoma were 2.0+/-0.7, 26+/-5.4, 41.2+/-10.1, 74.7+/-9.3 respectively. 3. There was statistically significant relationship between TP and Ki-67 expression. CONCLUSION: The above results indicates that the angiogenic activities and cellular proliferation indices increase according to the invasiveness of cervical cancer. We were able to reveal the expression of TP and Ki-67 and their relationship in cervical carcinoma.
Antibodies, Monoclonal ; Cell Proliferation ; Chungcheongnam-do ; Epithelium ; Thymidine Phosphorylase* ; Thymidine* ; Uterine Cervical Neoplasms ; Uterus

BACKGROUND: Thymidine phosphorylase (TP) is an enzyme catalyzing the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate. TP plays a role in angiogenesis. Evidences suggest that infiltrating inflammatory cells adjacent cancer cells may affect tumor cell behavior. To evaluate each of these significances of TP expression in cancer cell and cancer-infiltrating inflammatory cells, we investigated TP expression patterns in cancer cells and infiltrating inflammatory cells adjacent cancer cells separately and the relationship between TP expression and angiogenesis or survival. METHODS: Immunohistochemistry assays were performed with anti-TP monoclonal antibody (Roche Japan) and anti-factor VIII polyclonal antibody (Dako) on 92 paraffin-embedded tissue samples from stomach cancer patients. A single pathologist scored the slides for percent positivity of tumor cells, intensity, localization and distribution of expression. TP reactivity in tumor cells (cancer) and infiltrating mononuclear cells adjacent cancer cells (matrix) was separately accessed. According to the pattern of TP expression, subjects were divided into 4 groups for further analysis: cancer(C;+)/matrix(M;+), cancer(+)/matrix(-), cancer(-)/matrix(+) and cancer(-)/matrix(-). With these 4 subsets of TP expression patterns, we evaluated cancer cell differentiation, intratumoral microvessel density, extent of tumor invasion, LN stage, and patient survival to find any differences among the subsets. RESULTS: Of 92 stomach cancer tissue, C/M(+/+), C/M(+/-), C/M(-/+), and C/M(-/-) were observed in 33patients, 19, 30, and 10, respectively. Microvessel density scores were higher in cancer(+)/matrix(-) group compared in cancer(-)/matrix(-) group (p=0.02). Of 4 TP expression subsets, other clinical factors such as histology, extent of tumor invasion, and LN metastasis were not associated with TP expression. CONCLUSION: This study suggested the TP in cancer-infiltrating inflammatory cell as well as cancer cells themselves may play an important role in angiogenesis as co-active factors in stomach cancer.
Cell Differentiation ; Humans ; Immunohistochemistry ; Microvessels ; Neoplasm Metastasis ; Prognosis* ; Stomach Neoplasms* ; Stomach* ; Thymidine Phosphorylase ; Thymidine* ; Thymine

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: Docetaxel (Taxotere(R)) and capecitabine are used in combination to treat advanced gastric cancer. Thymidine phosphorylase (TP) is an essential enzyme for the activation of capecitabine in tumors. This study sought to identify the best combination therapy with capecitabine and using two different schedules for docetaxel, a TP up-regulator, to enhance capecitabine's efficacy. METHODS: The human gastric cancer cell line SNU-484 was cultured and docetaxel (2 microgram/ml) was added to the 24-well plates that contained 5 x 10(5) cells/well. The total RNA was isolated and RT-PCR was done to identify the TP expression. Four- or five-week-old BALB/c-nu/nu mice were subcutaneously inoculated with the SNU-484 cells. The nude mice were divided into two groups and they were given capecitabine 539 mg/m2 p.o. from days 1 to 14: Group 1 was given docetaxel 15 mg/m2 i.v. on day 1; Group 2 was given docetaxel 7.5mg/m2 on days 1 and 8. Tumor tissues were excised on days 1, 8 and 15 to measure the TP and bcl-2 levels. RESULTS: TP was expressed 2 hours after docetaxel administration. Group 2 had a higher TP concentration in the tumor tissues and a better antitumor effect than did Group 1. There was no difference in the bcl-2 concentration in the two groups. CONCLUSION: These results suggest that docetaxel stimulates the TP expression in tumor tissues and it enhances the antitumor activity of capecitabine. A weekly docetaxel injection with capecitabine administration can be used to treat gastric cancer more effectively than when docetaxel is injected once per cycle. Capecitabine had no bcl-2 suppressive effect in this study.
Animals ; Appointments and Schedules* ; Capecitabine ; Cell Line* ; Heterografts* ; Humans ; Mice ; Mice, Nude* ; RNA ; Stomach Neoplasms* ; Thymidine Phosphorylase* ; Thymidine*

PURPOSE: To study the efficacy of capecitabine or S-1 plus oxaliplatin (CAPOX or SOX) for treating thymidine phosphorylase (TP)- or dihydropyrimidine dehydrogenase (DPD)-positive advanced gastric cancer.MATERIALS AND METHODS: Eighty-six patients with stage IIIC to IV gastric cancer were assessed for TP and DPD expression by immunohistochemistry. The association between CAPOX or SOX efficacy and TP/DPD expression was retrospectively analyzed.RESULTS: There were no significant differences in the objective remission rate (ORR, 52.27% vs. 47.62%; P>0.05), disease control rate (72.73% vs. 73.81%, P>0.05), progression-free survival (hazard ratio [HR], 1.119; 95% confidence interval [CI], 0.739–1.741; P=0.586), and overall survival (OS; HR, 0.855; 95% CI, 0.481–1.511; P=0.588) between CAPOX and SOX. A higher number of stage IV patients showed TP positivity, while DPD-positive patients predominantly showed intestinal type of gastric cancer. In TP-positive patients, the ORRs associated with CAPOX and SOX treatments were 57.14% and 38.10%, respectively; OS was better with CAPOX than with SOX (HR, 0.447; 95% CI, 0.179–0.978; P=0.046). Among DPD-positive patients, the SOX treatment-associated ORR (60.87%) was significantly higher than the CAPOX treatment-associated ORR (43.48%). Furthermore, SOX treatment resulted in better OS than did CAPOX treatment (HR, 2.020; 95% CI, 1.019–4.837; P=0.049).CONCLUSIONS: No significant difference in clinical efficacy was found between CAPOX and SOX. TP-positive patients might respond better to CAPOX while DPD-positive patients may respond better to SOX. Our findings might serve as a guide for personalized chemotherapy for gastric cancer.
Capecitabine ; Dihydrouracil Dehydrogenase (NADP) ; Disease-Free Survival ; Drug Therapy ; Humans ; Immunohistochemistry ; Retrospective Studies ; Stomach Neoplasms ; Thymidine Phosphorylase ; Thymidine ; Treatment Outcome

OBJECTIVETo investigate the inhibiting impact of 5'-deoxy-5-fluorouridine (5'-DFUR) on human colon carcinoma cell line LOVO after transfection of thymidine phosphorylase (TP) cDNA.

METHODSTP cDNA was transfected into human colon carcinoma cell line LOVO with lentiviral vector pLenti6.3_MCS_IRES2-EGFP, and the transfection efficiency was analyzed by flow cytometry. TP mRNA and protein expressions were detected by RT-PCR and Western blotting respectively. The IC50 of 5'-DFUR on TP-transfected LOVO and parental cell were evaluated by MTT assay. The volumes of 5-FU converted from 5'-DFUR in media, where TP-transfected and parental LOVO were cultured, were detected by HPLC.

RESULTSThe stable transfectants passed 5 generations were obtained and the transfection rate was 95%. Compared with parental cell, the RQ values of mRNA expression in TP-transfected LOVO was (282.5±86.8) folds higher significantly (P<0.01), also the TP protein expression of TP-transfected LOVO was obviously up-regulated as compared to parental cells. The IC50 value of 5'-DFUR of TP-transfectants was (1087.7±89.1) μmol/L, less than (1607.3±56.8) μmol/L of parental cells significantly (P<0.01), while there was no significant difference between parental cells and vector-transfectants [(1699.5±38.7) μmol/L, P>0.05]. HPLC revealed that when medium was added with 0, 500, 1000, and 2000 μmol/L of 5'-DFUR respectively, 0, 2.10, 3.13, and 7.19 μmol/L of 5-FU was found in the parental cells culture, while 0, 22.16, 30.94 and 40.02 μmol/L of 5-FU was found in TP-transfectants culture, but no 5-FU was found in the vector-transfectants culture.

CONCLUSIONTP cDNA transfection into LOVO can up-regulate the TP mRNA and protein expressions, increase the 5-FU converted from 5'-DFUR, and enhance the cytotoxic effect of 5'-DFUR on the LOVO cells.

Cell Line, Tumor ; Colonic Neoplasms ; pathology ; DNA, Complementary ; genetics ; Floxuridine ; pharmacology ; Humans ; Thymidine Phosphorylase ; genetics ; Transfection

BACKGROUND AND OBJECTIVES: Tumor angiogenesis is an essential process required for growth and metastasis in cancer. Vascular endothelial growth Factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) are known to be angiogenetic factors. The objectives of this study were to measure the expression of VEGF, PD-ECGF and microvessel density (MVD) in head and neck squamous cell carcinoma (HNSCC) and compare them to normal larynx. We also evaluated relationships of VEGF, PD-ECGF and MVD to clinicopathologic findings in HNSCC. MATERIAL AND METHODS: The expression of VEGF, PD-ECGF and MVD were evaluated by immunohistochemical staining of 26 cases of HNSCC and 6 cases of normal larynx. RESULTS: The expressions of VEGF, PD-ECGF and MVD in HNSCC were significantly higher than in the normal control (p<0.05). MVD were significantly correlated with VEGF and PD-ECGF expressions in HNSCC (p<0.05). The VEGF, PD-ECGF expression and MVD correlated with many clinicopathologic findings in HNSCC. CONCLUSION: These results suggest that VEGF and PD-ECGF are involved in angiogenesis and are related to clinicopathologic findings of HNSCC. Furthermore, we propose that expressions of VEGF, PD-ECGF and MVD to be investigated more in the future as prognostic indicators of HNSCC.
Carcinoma, Squamous Cell* ; Head* ; Larynx ; Microvessels ; Neck* ; Neoplasm Metastasis ; Thymidine Phosphorylase* ; Vascular Endothelial Growth Factor A*

PURPOSE: Angiogenesis plays an important role in the growth and metastasis of solid tumors. It has been recently reported that thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor. In this study, we analyzed the correlation between dThdPase activity and neovascularization, and also determined their prognostic significance by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining in patients with gastric carcinoma. METHODS: The medical records of 57 patients with gastric carcinoma who underwent radical gastrectomy were retrospectively reviewed. Primary tumors were studied by immunohistochemical staining with anti-PD-ECGF/dThdPase and anti- CD34 monoclonal antibodies. The dThdPase activity level was also analyzed by ELISA. Microvessels were assessed by immunostaining endothelial cells for CD34. We counted the number of microvessels in the tumors of the patients. RESULTS: The dThdPase activity of tumor tissues (82.4+/-66.2 unit/mg protein) was significantly higher than that of normal mucosas (8.9 +/- 18.2 unit/mg protein) (P < 0.0001). Immunohistochemical staining with anti-dThdPase and anti-CD34 monoclonal antibodies was performed in 57 gastric carcinoma tissue samples. Positive dThdPase expression was observed in 24 (42.1%) tumors. The average number of cells expressing CD34 was significantly higher in the dThdPase- positive carcinomas (44.4+/-15.3) than in the dThdPase- negative carcinomas (30.7+/-15.8)(P<0.003). The expression of dThdPase was significantly associated with the intratu moral microvessel counts (P=00005). The patients with dThdPase-positive carcinoma showed a significantly worse prognosis than those with dThdPase-negative carcinoma (P=0.034). CONCLUSION: These results suggest that dThdPase plays a role in the promotion of angiogenesis, and that it is a possible candidate as a prognostic factor in human gastric carcinomas.
Antibodies, Monoclonal ; Endothelial Cells ; Enzyme-Linked Immunosorbent Assay ; Gastrectomy ; Humans* ; Medical Records ; Microvessels ; Mucous Membrane ; Neoplasm Metastasis ; Prognosis ; Retrospective Studies ; Thymidine Phosphorylase* ; Thymidine*