Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

OVERVIEW: Clinical indications for the use of interferons (IFNs) for cancer continue to expand and will likely continue to do so. IFNs have been approved for clinical use by the United States Food and Drug Administration for chronic myelogenous leukemia (CML), hairy cell leukemia, follicular lymphomas, Kaposi's sarcoma in the setting of AIDS, and melanoma for patients at high risk for recurrence after surgery. In addition, as a result of their antiviral activity, IFNs result in control of chronic active hepatitis and recurring papillomas that may reduce cancer development resulting from these processes and their underlying viruses. For almost all of these indications, therapeutic activity has been established from well-conducted, international phase III clinical trials. IFNs were the first successful biological therapy for human malignancy; they can synergize to produce tumor regression with surgery and chemotherapy and can potentiate other cytokines and monoclonal antibodies. IFNs and cytokines can modulate gene expression, resulting in enhanced immune effector-cell number, cytotoxicity, antigen expression, and production of other cytokines. IFNs have pleiotropic effects on cellular function, including influences on growth, differentiation, and immunologic function. For greatest effects, IFNs are used in combination with other modalities of therapy. This increases the effect of IFNs or allows IFNs to increase the effects of other therapies. Cytosine arabinoside improves the therapeutic effectiveness of IFNs in CML, and IFN-&agr;2b improves the prognosis, survival, and quality of life after surgery for high-risk patients with melanoma. Gene modulation by IFN-&agr; or IFN-&bgr; of thymidine phosphorylase, an enzyme important in DNA synthesis, has been suggested to be the basis for enhancing 5-fluorouracil (5-FU) effectiveness in preclinical models and may augment effectiveness in adenocarcinomas. IFNs increase the expression of some tumor-associated antigens that could be of benefit for combination use with monoclonal antibodies for imaging or therapy.
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PMID:Gene Regulation and Clinical Roles for Interferons in Neoplastic Diseases. 1038 4

Expression of matrix metalloproteinases (MMPs) plays an essential role in tumor metastasis and invasion through the degradation of extracellular matrix (ECM). MT1-MMP (membrane type 1 matrix metalloproteinase), a membrane-type MMP, is responsible for the activation of MMP2. In this study the significance of MT1-MMP expression in human breast tumors was investigated by immunocytochemical assay, and its correlation with clinicobiological features was analyzed. MT1-MMP expression was detected in tumor cells and/or stromal cells, and there was a strong correlation between the expressions of MT1-MMP in the two cell types. Out of 183 primary tumors, 103 (56.2%) showed positive staining of MT1-MMP in tumor cells. MT1-MMP expression showed no significant correlation with any of the clinicobiological parameters examined, including hormone receptor status and angiogenesis. In postoperative survival analysis, MT1-MMP expression itself was not a significant prognostic factor. However, in the particular subgroup with the accumulation of thymidine phosphorylase (TP)-positive stromal cells, which have been activated by various stimuli, such as cytokines and hypoxia, MT1-MMP expression had a significant prognostic value. These data suggested that MT1-MMP might function cooperatively with tumor-associated stromal cells for the progression of breast cancer.
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PMID:Significance of membrane type 1 matrix metalloproteinase expression in breast cancer. 1039 Oct 91

Angiogenesis is essential for tumour growth and important in metastasis and for prognosis in invasive carcinoma of the breast. Two patterns of increased vascularity have been shown in mammary ductal carcinoma in situ (DCIS): a cuff of vessels close to the involved ducts, and vessels in the interductal stroma. Inflammation may potentially promote angiogenesis by release of angiogenic factors and digestive enzymes. A correlation has previously been found between the intensity of perivascular inflammation and stromal vascularity in DCIS, but no strong relationship has been observed between inflammation and angiogenesis in invasive carcinoma. Tumour angiogenesis is regulated by a number of angiogenic factors, including thymidine phosphorylase (platelet-derived endothelial cell growth factor), which is expressed at high levels in macrophages. Using immunohistochemical methods, thymidine phosphorylase expression and vascularity have been studied in DCIS (n = 34) and invasive carcinoma (n = 32). Stromal vascularity in DCIS was associated with thymidine phosphorylase expression in the perivascular inflammatory cells and in the cytoplasm of carcinoma cells. In invasive carcinoma, no relationship was found between vascularity and thymidine phosphorylase expression in either the carcinoma or the inflammatory cells. This study suggests that thymidine phosphorylase expression in both inflammatory and carcinoma cells may contribute to one of the patterns of vascularity in DCIS, but not in invasive disease.
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PMID:Angiogenesis and expression of thymidine phosphorylase by inflammatory and carcinoma cells in ductal carcinoma in situ of the breast. 1039 80

A 79-year-old male was admitted to our hospital for further examination on gastric carcinoma (1' type) in the cardia. The histology of biopsied tissue was moderately differentiated adenocarcinoma (tub2). The patient refused a gastrectomy and received three cycles of local injection therapy with OK-432 + Beriplast into the tumor. However, the tumor showed no decrease in size. Considering the quality of life, the patient was given out patient treatment with 5'-DFUR (Furtulon, 800 mg/day). Three months later, the patient showed a partial response (PR) on the basis of gastric X-ray and endoscopic findings. No adverse reactions to the drug were seen. The patient has been receiving the same drug since then, and has continued to show PR for 15 months. Biopsied tissues were checked immunohistochemically for expression of thymidine phosphorylase (TdRPase), and changes in tissue TdRPase level were examined by ELISA. The TdRPase level decreased with shrinking of the tumor. These results suggest that the shrinking of tumor following 5'-DFUR therapy is closely related to TdRPase.
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PMID:[A case of gastric carcinoma treated effectively with 5'-DFUR]. 1041 Jan 55

We studied the antitumor activity and toxicity of ZD1694 (tomudex), a specific inhibitor of thymidylate synthase (TS), in nude mice bearing human head and neck squamous cell carcinoma A253 and FaDu xenografts. Mice were treated by single i.v. push (i.v. x 1), i.v. push once a week for 3 weeks (weekly x 3), and i.v. push once a day for 5 days (daily x 5), and the maximum tolerated doses (MTDs) of ZD1694 were 300 mg/kg, 60 mg/kg/week, and 30 mg/kg/day, respectively. ZD1694 was moderately active against both A253 and FaDu xenografts. Antitumor activity was schedule-dependent in both tumors: weekly x 3 > or = i.v. x 1 >> daily x 5. In contrast, the rank order of toxicity was daily x 5 >> weekly x 3 > or = i.v. x 1. ZD1694 at the MTD produced 20% complete tumor regression and 20% partial tumor regression (PR) with i.v. x 1 and weekly x 3 schedules and 12-day tumor growth delay with daily x 5 schedule against FaDu xenografts. No complete tumor regression was achieved with ZD1694 with any schedule against A253; a 20% PR, 40% PR, and 10-day tumor growth delay were observed with i.v. x 1, weekly x 3, and daily x 5 schedules, respectively. The data indicate that ZD1694 was slightly more effective against FaDu than against A253. Of interest and potential clinical importance was the observation that ZD1694 was still active at doses lower than the MTD (> or =1/3 MTD), which showed a high therapeutic index and wide safety margin. Study of ZD1694 compared with 5-fluorouracil and 5-fluoro-2'-deoxyuridine at the MTD revealed that the antitumor activity of ZD1694 was comparable with or superior to 5-fluorouracil and 5-fluoro-2'-deoxyuridine against both A253 and FaDu xenografts, with less toxicity. High plasma thymidine in mouse relative to human (approximately 1.3 microM and <0.1 microM, respectively) may complicate the study of antitumor activity and toxicity of TS inhibitors with human tumor xenografts grown in the mouse. To test this hypothesis, we preadministered methoxypolyethyleneglycol-conjugated thymidine phosphorylase (MPEG-TPase; 2500 units/kg/dose) to reduce mouse plasma thymidine, then treated with various doses of ZD1694 using the daily x 5 or i.v. x 1 schedules in the A253 tumor model. MPEG-TPase significantly increased the toxicity of ZD1694; the MTD of ZD1694 plus MPEG-TPase was reduced 3- and 10-fold compared with ZD1694 alone for i.v x 1 and daily x 5 schedules, respectively. However, preadministration of MPEG-TPase did not potentiate the antitumor activity of ZD1694 with either schedule. The data indicate that the study of TS inhibitors in rodent models may not be suitable for predicting a safe dose for clinical study. However, rodent models, particularly human tumor xenografts, are still useful models for evaluation of antitumor activity and schedule selection for TS inhibitors.
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PMID:Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine. 1043 Jan

5-Fluorouracil (5-FU) plays an important role in the treatment of several tumor types, particularly colorectal cancer and breast cancer. Xeloda (capecitabine; 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl-cytidine]) is a new rationally designed fluoropyrimidine carbamate. It is administrated orally and after absorption it is first metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase from the liver and then converted to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase from the liver and tumor tissues. Finally, thymidine phosphorylase (TP) converts 5'-DFUR to 5-FU. TP is more active in tumor tissues than in normal tissue. This tissue localization pattern results in preferential metabolism and generates higher levels of 5-FU in malignant tissue, thus enhancing efficacy but minimizing side effects. The tumor tissue selectivity was confirmed in a study of 19 patients with colorectal cancer. After Xeloda administration, concentrations of 5-FU were 2.5 times higher in the primary tumor compared with adjacent healthy tissue. Xeloda was highly active in human tumor xenografts. It was more active than 5-FU, 5'-DFUR and tegafur plus uracil (UFT) and had a better therapeutic index. Xeloda also demonstrated synergistic or additive activity when used in combination with cyclophosphamide, methotrexate, doxorubicin, paclitaxel and docetaxel. This may be in part a result of up-regulation of TP by the cytotoxic agents. Phase I and II clinical trials have shown that Xeloda is active across a range of tumor types, and phase III studies are ongoing.
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PMID:Rational design of new tumoractivated cytotoxic agents. 1043 11

In this study, we obtained fresh samples of tissue (tumors, adjacent normal mucosas, and metastatic lymph nodes) from 64 patients (metastatic lymph nodes were obtained from 16 patients) with esophageal cancer who underwent esophagectomy between 1993 and 1998. The thymidine phosphorylase (dThdPase) levels of tumors as determined by the ELISA method were compared with clinicopathological findings of tumors and were evaluated for their usefulness as a prognostic parameter for these patients. The dThdPase levels of tumors (221 +/- 21 U/mg protein) and metastatic lymph nodes (253 +/- 51 U/mg protein) were significantly higher than the dThdPase level of normal mucosas (53 +/- 7 U/mg protein, p < 0. 001). The dThdPase levels of tumors did not correlate with the histopathological grading of tumors, the depth of tumor invasion, and lymph node metastasis. The 3-year survival rate of 32 patients with a high level of dThdPase (42%) was not different from that of 32 patients with a low level of dThdPase (52%, p = 0.267). Moreover, the dThdPase level of tumors was not an independent prognostic factor for patients with esophageal cancer. These findings suggest that the level of dThdPase activity in esophageal cancers may not correlate with tumor progression and may not be a useful prognostic marker for patients with esophageal squamous cell carcinoma.
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PMID:Clinical significance of the detection of thymidine phosphorylase activity in esophageal squamous cell carcinomas. 1044 95

The enzyme, thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF), which acts as a potent angiogenic factor. The present study immunohistochemically examined the expression of dThdPase in human colorectal mucosa, adenomas and carcinomas, as well as six cultured colorectal carcinoma cell lines, in terms of intratumoral microvessel density (IMVD) and P53 expression. Thymidine phosphorylase was observed in lymphocytes, fibroblasts and macrophages, as well as smooth muscle cells and Schwann cells in the peripheral nerve fibers. The dThdPase-positive stromal cells apparently outnumbered the normal epithelial cells, adenoma and carcinoma cells with dThdPase. Weak but obvious cytoplasmic immunoreactivity was noted in a few normal colonic epithelia, predominantly the upper surface area, while a few adenoma cells showed weak nuclear immunostaining for dThdPase in six (24%) of the 25 colonic adenomas. Expression of dThdPase was noted in 33 (73.3%) of the 45 Dukes A and B, 14 (51.9%) of the 27 Dukes C and 14 (56.0%) of the 25 Dukes D carcinomas. The mean IMVD was 84.0 +/- 26.2 in the 36 dThdPase-negative carcinomas and 97.9 +/- 31.6 in the 61 dThdPase-positive carcinomas, the value being significantly higher in the latter group (P < 0.05). The frequency of dThdPase expression was significantly lower in the P53-negative carcinomas than in the positive carcinomas (P < 0.05). Western blot analysis showed the highest expression of dThdPase in LoVo carrying the wild-type p53 gene, followed by Colo201, Colo320, DLD-11 and WiDr carrying the mutated gene. These results indicate that: (i) the main source of dThdPase is stromal cells, including lymphocytes and macrophages in both colorectal normal and carcinoma tissues; (ii) dThdPase may take part in the induction of intratumoral microvessels, regardless of tumor stage; and (iii) expression might be modulated by not only P53 but also other molecules.
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PMID:Thymidine phosphorylase expression in human colorectal mucosa, adenoma and carcinoma: role of p53 expression. 1046 91

The object of this study was to clarify the association of angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (dThdPase) with clinicopathological factors including tumor angiogenesis and patient outcome in endometrial cancer. There was no correlation between the expression of PD-ECGF in cancer cells and any of the clinicopathological variables. Immunopositivity for PD-ECGF in stroma cells was significantly higher in poorly differentiated adenocarcinomas. The microvessel counts correlated with PD-ECGF positive stroma cells (p<0.0001). Disease-free survival was significantly worse in patients with marked PD-ECGF expression in stromal cells and high microvessel count. A multivariate analysis using Cox's proportional hazard model showed that high microvessel counts independently predicted disease-free survival as well as stage and myometrial invasion. The expression of PD-ECGF in stroma cells may play a crucial role in the promotion of angiogenesis. Tumor angiogenesis can be used to predict prognosis in patients with endometrial cancer.
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PMID:Angiogenesis and platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in endometrial cancer. 1049 62

5'-Deoxy-5-fluorouridine (5'-dFUrd) is a prodrug of 5-fluorouracil (5-FUra) activated by pyrimidine nucleoside phosphorylase (PyN Pase), mainly by uridine phosphorylase (Urd Pase) in rodents and by thymidine phosphorylase (TdR Pase) in humans, which is preferentially located in tumor tissues compared to normal tissues. It has been reported that PyN Pase is induced by cytokines such as tumor necrosis factor (TNF), interleukin-1alpha (IL-1alpha) and interferon (IFN). Thymosin is a glycoprotein extract obtained from the calf thymus and is a potent immunopotentiating preparation. In this study, the antiproliferative activity of 5'-dFUrd used in combination with thymosin fraction 5 (TF5) was investigated in mouse bladder cancer cell line MBT-2 in vitro and in vivo. In vitro TF5 enhanced the activity of 5'-dFUrd by up to 4.11-fold, whereas the activity of other cytostatics such as 5-FUra, mitomycin C, adriamycin, cis-platinum, etoposide, vinblastine and methotrexate was not changed. In vivo when the effects of combination therapy with 5'-dFUrd and TF5 in C3H/HeN mice implanted with MBT2 were studied, tumor growth was not suppressed by TF5 alone while tumor growth was suppressed to some degree by 5'-dFUrd alone. However, tumor growth suppression was enhanced when 5'-dFUrd was used in combination with TF5. In order to investigate this mechanism, Urd Pase in MB2 was measured, and it was found that TF5 increased enzyme activity by up to 1.8-fold in MBT2. This increased susceptibility might be a result of the induction of Urd Pase, which is the essential enzyme for the conversion of 5'-dFUrd to 5-FUra. These results suggested that the therapeutic benefit of 5'-dFUrd would be improved by its use in combination with TF5 and the modulation of converting enzymes for antitumor prodrugs could be a novel therapeutic strategy for treating human cancers.
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PMID:Augmentation of antitumor activity of 5'-deoxy-5-fluorouridine by thymosin fraction 5 in mouse bladder cancer cells in vitro and in vivo. 1053 Jul 79


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