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)

We analyzed the interim results of prognostic significance of pyrimidine nucleoside phosphorylase (PyNPase), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) in 5-FU-based chemotherapy for breast cancer. In surgical specimens of tumor tissues and normal mammary gland tissues from 102 breast cancer patients, TS, PyNPase, and DPD activities were measured, and p53 and c-erbB-2 overexpression were also examined. TS, d-Thd-Pase/Urd-Pase (PyNPase), and DPD activities were significantly higher in tumor tissues than in normal tissues. There was a strong correlation between d-Thd-Pase and Urd-Pase in tumor tissues. No relationship was found between patient characteristics and any of the enzyme activities. PyNPase activities were significantly higher in the tissues having a c-erbB-2 overexpression of 75% (4+) or more than in those having less than 75%, and the tissues with a p53 of 50% (3+) or more had significantly higher TS activities than those with less than 50%. However, the other parameters showed no significant difference. The data obtained so far suggest no clear correlation between the activity of any of these enzymes and prognosis.
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PMID:[Significance of tissue PyNPase, TS, and DPD activities in breast cancer]. 1221 67

This study was designed to investigate the role of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) on tumour progression and sensitivity to 5'-deoxy-5-fluorouridine (5'-DFUR). Tumour tissue was obtained from surgically resected samples from 93 patients with primary gastric cancer. Tumour TP and DPD expression levels were determined by the enzyme-linked immunosorbent assay (ELISA) system and compared with several clinicopathological factors and in vitro sensitivity to 5'-DFUR. DPD showed no correlation with any clinicopathological factors. However, the TP level was significantly correlated with the depth of tumour, lymphatic invasion and venous invasion. In comparison with 5'-DFUR sensitivity, there was a weak inverse correlation between the DPD level and the sensitivity to 5'-DFUR (r(s)=-0.361). Furthermore, the TP/DPD ratio showed a significant correlation with 5'-DFUR sensitivity (r(s)=0.634). In a subgroup of patients with postoperative 5'-DFUR administration, the survival rate was significantly better in patients with a high TP/DPD ratio (n=8) than in those with low TP/DPD ratio (n=14) (P=0.0140). These results suggest that sensitivity to 5'-DFUR is predictable by measurement of both TP and DPD levels.
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PMID:Role of thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumour progression and sensitivity to doxifluridine in gastric cancer patients. 1246 Jul 81

Mechanisms of anti-tumor action of 5-fluorouracil (5-FU) are presumed to inhibit DNA synthesis and RNA function, and the balance of these mechanisms is presumed to depend on the modalities of administration. On the other hand, variability of 5-FU sensitivity of the tumors is also presumed to depend on the enzymes of 5-FU metabolism (e.g. dihydropyrimidine dehydrogenase; DPD, rate limiting enzyme of catabolism) and action target (e.g. thymidylate synthase; TS). We studied the effects of modalities of administration and enzyme activities related to metabolism and target of 5-FU on the mechanism of anti-tumor action in patients with colorectal cancer. Thirty-eight patients who were diagnosed at stage II to IV preoperatively were enrolled. Patients were randomly assigned to receive 24-h protracted IV infusion of 5-FU at 320 mg/m(2)/day for 5 days (CIV group: 18 patients) or 10-min bolus IV infusion of 5-FU at the same dosage for 5 days (BIV group: 20 patients) administered from the 5th preoperative day. Specimens from the tumor and non-tumor regions were obtained by operation. F-RNA (fraudulent-RNA, or 5-FU in RNA) concentration, an indicator for action of 5-FU to RNA, and the enzyme activities of DPD and TS, an indicator for action of 5-FU to DNA, in the collected specimens were measured by GC-MS or RI-HPLC. F-RNA concentration (ng/mg-RNA) in the tumor and non-tumor region in the CIV group was 100.58+/-16.88 and 50.11+/-6.03, respectively, with a significant difference between them (P<0.05), and in the tumor and non-tumor region in the BIV group was 195.32+/-16.26 and 121.05+/-10.62, respectively, with a significant difference between them (P<0.01). F-RNA concentration in the tumor and non-tumor regions in the BIV group was significantly higher than those in the CIV group (P<0.05). DPD activity and TS activity were not significantly different between the CIV and the BIV groups in the tumor and non-tumor region, respectively. F-RNA concentration was negatively correlated to DPD activity (r=-0.540, P<0.05) in the tumor region in the CIV group. F-RNA was not correlated to DPD activity in the non-tumor region in the CIV group or in the tumor and non-tumor region in the BIV group. F-RNA was not correlated to TS activity in the tumor or non-tumor region of the two groups. DPD activity was not correlated to TS activity in the tumor or non-tumor region of the two groups. BIV inhibited RNA function more potently than CIV and this was not dependent on TS or DPD activity. As for the inhibition of DNA synthesis, other indicators should be considered further.
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PMID:Differential effects of two fluorouracil administration regimens for colorectal cancer. 1246 54

In the United States, tumors of the central nervous system remain the third leading cancer-related cause of death in young adults with a median survival time of < 1 year. A recent case study suggested that Capecitabine (a novel, fluoropyrimidine prodrug) may be effective in the treatment of brain metastases. Pharmacogenomic studies have correlated the antitumor response to Capecitabine with the expression of the drug metabolizing enzymes thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). In the current study, we examined TP and DPD expression in normal human brain tissues and in glioblastoma multiforme, the most common and malignant type of brain tumor. Because previous reports suggest a tumor necrosis factor (TNF)-alpha-mediated increase in TP expression after irradiation (a current standard of care for glioblastoma multiforme), we also examined the effect of irradiation on the expression of TP, DPD, and TNF-alpha in both irradiated and lead-shielded contralateral U87MG glioma xenografts within the same animal. Expression levels were determined using real-time quantitative PCR as described previously. Results demonstrate an approximately 70-fold increase in TP mRNA levels 4 days after irradiation, relative to initial control levels. Interestingly, TP mRNA in the lead-shielded tumors (contralateral to irradiated tumors) increased approximately 60-fold by day 10 relative to initial control levels. Elevated TP levels were sustained for 20 days in irradiated xenografts but began to decrease after 15 days in the shielded/contralateral tumors, returning to baseline by 20 days. TP mRNA levels in normal mouse liver were unaltered, suggesting a tumor-associated effect. TNF-alpha mRNA levels did not increase after irradiation; therefore, mRNA expression of 11 additional cytokines [interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, and IFN-gamma] in both the irradiated and shielded xenografts was quantitated. Results demonstrated increased levels of IFN-gamma, IL-10, and IL-1 alpha by 6.3-, 3.7-, and 1.6-fold, respectively, in irradiated tumors only. DPD mRNA levels did not change after irradiation. The tumor-associated induction of TP in irradiated and lead-shielded tumors within the same animal may have significant implications for the combined modality treatment of cancer patients with Capecitabine in conjunction with radiotherapy and may apply to the treatment of distant tumors and or metastatic disease.
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PMID:Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. 1248 38

We used real-time reverse-transcription polymerase chain reaction (RT-PCR) to assay expression of the mRNA of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in gastric cancer tissue with the objective of establishing a system to measure TS and DPD in ultra-low-volume samples. Nude mouse xenografts of 5 human gastric cancer cell lines and 85 clinical samples were used as the specimens in this study. Sensitivity to 5-fluorouracil (5-FU) was determined on the basis of the relative tumor proliferation rate in mice and the results of ATP assay using serum-free cultures of the clinical samples. mRNA expression was measured in tumor tissue by real-time RT-PCR using the ABI PRISM 7700 system. The values for expression of the mRNA for TS and DPD were corrected according to the level of glyceraldehyde-3-phosphate dehydrogenase mRNA expression. The xenografts yielded correlations between TS and DPD mRNA expression and the activity of the enzymes (TS: rs=0.700, DPD: rs=0.900), and an inverse correlation was noted between the mRNA levels and sensitivity to 5-FU (TS: rs=-0.900, DPD: rs=-0.800). The clinical samples showed an inverse correlation between 5-FU sensitivity and mRNA expression (TS: rs=-0.518, DPD: rs=-0.564). Sensitivity to 5-FU was noted only in cases in which TS mRNA expression and DPD mRNA expression were both low. Real-time RT-PCR can provide a highly sensitive assessment of TS and DPD mRNA expression in gastric cancer, and it was useful for predicting 5-FU sensitivity.
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PMID:Quantitative measurement of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level in gastric cancer by real-time RT-PCR. 1249 74

Survival of patients with advanced gastric cancer with Krukenberg's tumor is poor. We report the case of a good response in a 37-year-old woman who had type 4 gastric cancer, diagnosed after the operation of Krukenberg's tumor, and then was treated with TS-1, a DPD inhibitory fluoropyrimidine, in combination with a low-dose cisplatinum (CDDP). Endoscopic gastric biopsy showed signet-ring cell adenocarcinoma and moderately differentiated tubular adenocarcinoma, and computed tomography (CT) showed the para-aortic lymph node metastasis before the chemotherapy. The patient was treated with two courses of TS-1 (100 mg/day, day 1-21) plus CDDP (10 mg/m2, day 1-5, 8-12, 15-19) with two-week interval. After the first course, gastric biopsy did not show any cancer cells and lymph node metastasis had disappeared. Serum CA19-9 decreased gradually week by week during the chemotherapy, even during the washout period after the first course, and was normalized after two courses. This case suggests that the combination of TS-1 and low-dose CDDP is effective against type 4 advanced gastric cancer.
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PMID:[A case of type 4 gastric cancer, diagnosed after operation for Krukenberg's tumor, treated by TS-1 plus low-dose cisplatinum]. 1261 Aug 79

A 68-year-old male with a history of gastric resection for gastric cancer underwent resection of the sigmoid colon for a sigmoid colon cancer in February, 2000. The cancer was classified as stage III b. After operation, l-LV + 5-FU therapy was administered, but metastases to the abdominal wall, right inguinal lymph node and spleen developed in succession, and resection was repeated. In October 2001, 1 year and 8 months after sigmoidectomy, however, multiple metastasis to the intraperitoneal lymph node had developed. As surgery was not indicated, TS-1/CDDP combined chemotherapy was started. TS-1 80 mg/day was administered for 4 weeks, the drug was withdrawn for 2 weeks and CDDP 80 mg was injected by intravenous drip at the 8th day of TS-1 administration, which was used as one course. From the second course after inception of the administration, CA19-9 decreased, and after the third course the upper intraperitoneal metastatic lesion disappeared on CT. CR has been continued for 4 months up to the present. Our results suggest a possibility that this therapy is effective not only for gastric cancer but also for colon cancer. This therapy can be administered at home. It is considered to be a useful therapy from the viewpoint of QOL as well. The high DPD activity of the tumor may have been one reason this treatment was effective. This case also seems significant from the viewpoint of attaining individualization of the drug selection in chemotherapy.
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PMID:[A case report--TS-1/CDDP combined chemotherapy found effective for metastatic recurrence after operation for colon cancer]. 1261 Aug 80

A series of tumor-activated prodrugs of the inhibitors of dihydropyrimidine dehydrogenase (DPD), an enzyme catabolizing 5-fluorouracil (5-FU: 4g), has been designed and synthesized. RO0094889 (11c) is a prodrug of 5-vinyluracil (4c), a known DPD inhibitor, and was designed to generate 4c selectively in tumor tissues by sequential conversion of 11c by three enzymes: esterase, cytidine deaminase and thymidine phosphorylase, the latter two of which are known to be highly expressed in various tumor tissues. When capecitabine (1), a tumor-activated prodrug of 5-FU, was co-administered orally with 11c, 5-FU in tumor tissues was significantly increased with only a slight increase of 5-FU in plasma as compared with oral capecitabine alone.
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PMID:Design and synthesis of the tumor-activated prodrug of dihydropyrimidine dehydrogenase (DPD) inhibitor, RO0094889 for combination therapy with capecitabine. 1261 10

The prognosis of patients with colorectal cancer is impacted by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Optimal postoperative management of patients who have undergone successful tumor resection involves the utilization of reliable determninants of prognosis to help select patients who would benefit from adjuvant treatment, while sparing others from drug-related adverse effects. Tailoring chemotherapy for patients with disseminated cancer, or for patients who receive adjuvant chemotherapy, is also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets, and drug transport molecules is an important contributing factor. The identification of genetic markers of response and prognosis will aid in the development of more individualized chemotherapuetic strategies for cancer patients. Potential prognostic indicators in colorectal cancer include oncogenes, tumor suppressor genes, genes involved in angiogenic and apoptotic pathways and cell proliferation, and those encoding targets of chemotherapy. Specifically, molecular markers such as deletion of 18q (DCC), p27 and microsatellite instability are promising as indicators of good or poor prognosis. Molecular determinants of efficacy and host toxicity of the most commonly used drugs in colorectal cancer, fluoracil, irinotecan and oxaliplatin, are being investigated. Alterations in gene expression, protein expression and polymorphic variants in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, dUTP nucleotidehydrolase and thymidine phosphorylase (for fluoropyrimidine-based chemotherapy), uridine diphosphate glucosyltransferase (UGT) 1A1 and carboxylesterase (for irinotecan therapy), and excision repair cross-complementing genes (ERCC1 and ERCC2) and glutathione-S-transferase P1 (for oxalilplatin-based regimens) may be useful as markers for clinical drug response, survival and host toxicity.
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PMID:Implications of genetic testing in the management of colorectal cancer. 1274 25

In the present study, in order to evaluate the feasibility of personalized chemotherapy, a prospective randomized pilot study was performed in 30 advanced or recurrent gastric cancer patients. As we have demonstrated previously, the expressions of mRNA from tumor biopsy samples for seven molecular markers, i.e., dihydropyrimidine dehydrogenase (DPD), glutathione S-transferase (GST)-pi, beta-tubulin (tub), O6-methylguanine-DNA methyltransferase (MGMT), multiple drug-resistant protein (MRP)-1, NADPH/quinone oxidoreductase (NQO)-1, and cytochrome p450 (P450), were examined by reverse transcription-polymerase chain reaction (RT-PCR) analysis and therapy was recommended in a flow chart that depended on the level of expression of these predictive molecular markers. We chose 12 therapeutic plans, including best supportive care (BSC). We treated 15 patients according to the gene expression profiles, and the remaining 15 patients (controls) were treated without recommended regimens, and the therapy was continued after the expression profiles were checked. Interestingly, 11 of 26 lesions (42.3%) responded after treatment given according to gene expression analysis; however, no clinical response was detected in the control group. The prediction of the response, including resistance, was successful in 75.9% by the gene expression profiles. Moreover, the survival of the patients with the recommended treatment was better than that of patients without a recommended protocol. These results indicate that personalized treatment may be beneficial for gastric cancer chemotherapy and further randomized trials should be carried out in the future.
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PMID:Future prospects of personalized chemotherapy in gastric cancer patients: results of a prospective randomized pilot study. 1277 25


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