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)

The pharmacological inactivation of dihydropyrimidine dehydrogenase (DPD) represents one strategy to improve 5-FU therapy, which historically has been associated with unpredictable pharmacological behavior and toxicity. This is principally due to high interpatient differences in the activity of DPD, the enzyme that mediates the initial and rate-limiting step in 5-FU catabolism. By inactivating DPD and suppressing the catabolism of 5-FU, eniluracil has dramatically altered the pharmacological profile of 5-FU. The maximum tolerated dose of oral 5-FU given with oral eniluracil (1.0 to 25 mg/m2) is substantially lower than conventional 5-FU doses. In the presence of eniluracil, bioavailability of 5-FU has increased to approximately 100%, the half-life is prolonged to 4 to 6 hours, and systemic clearance is reduced > 20-fold to values comparable the glomerular filtration rate (46 to 58 mL/min/m2). Renal excretion (approximately 45% to 75%), instead of DPD-related catabolism, is the principal route of elimination of oral 5-FU given with eniluracil. Chronic daily administration of oral 5-FU 1.0 mg/m2 twice daily with eniluracil 20 mg twice daily produces 5-FU steady-state concentrations (8-38 ng/mL) similar to those achieved with protracted intravenous administration on clinically relevant dose-schedules. On a daily x 5 regimen, higher 5-FU AUC values are related to neutropenia, whereas elevated 5-FU AUC and steady-state concentrations are related to diarrhea when oral 5-FU is given daily with eniluracil on a chronic schedule. The pharmacokinetic behavior of oral eniluracil is similar to that for oral 5-FU. Administration of eniluracil 10 to 20 mg twice daily completely inactivates DPD activity both in peripheral blood mononuclear cells and in colorectal tumor tissue, and prolonged inhibition of DPD after discontinuation of eniluracil treatment has been noted. In the presence of eniluracil, oral administration of 5-FU is feasible and variation in 5-FU exposure is reduced, with the anticipation of further reduction in variation as dosing guidelines based on renal function are formulated.
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PMID:Pharmacology of fluorinated pyrimidines: eniluracil. 1108 73

Eniluracil (776C85, GW776) inactivates dihydropyrimidine dehydrogenase (DPD), the principal enzyme of 5-fluorouracil (5-FU) catabolism. Inactivation of DPD eliminates a potential mechanism for tumor 5-FU resistance and permits achievement of reliable and predictable pharmacokinetics following oral 5-FU administration. Eniluracil/5-FU has demonstrated efficacy as monotherapy in patients with a variety of solid tumors when given on a 5 or 28-day dosing schedule. The primary and dose-limiting toxicity is myelosuppression with the 5-day schedule and diarrhea with the 28-day schedule. The frequency of hand-foot syndrome is minimal with either schedule. Phase III pivotal registration-directed studies with eniluracil/5-FU given by the 28-day schedule are ongoing or planned for the near future in patients with advanced colorectal, breast and pancreatic cancer.
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PMID:Clinical development of eniluracil/fluorouracil: an oral treatment for patients with solid tumors. 1108 74

The value of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) activity in metastatic liver tumor from colorectal cancer as predictive parameters for hepatic artery infusion (HAI) chemotherapy with 5-FU was investigated. Thirteen patients with metachronous liver metastases underwent hepatic resection and primary site colectomy. We measured TS and DPD activity in normal colonic mucosa, primary colon tumor, and metastatic liver tumor in these patients. The TS (pmol/g-tissue) of primary tumor, metastatic tumor, and normal colonic mucosa was 6.6 +/- 1.40 (mean +/- SE), 3.2 +/- 0.83 and 2.5 +/- 0.83 respectively. The DPD (pmol/min/mg/protein) of primary tumor, metastatic tumor, and normal colonic mucosa was 31.7 +/- 5.49, 82.1 +/- 12.5 and 50.6 +/- 8.46, respectively. There was significant relationship between DPD activity level and recurrence. It is suggested that 5-FU catabolism in metastatic liver tumor was increased, and DPD activity may be a valuable predictive marker for tumor response to HAI therapy.
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PMID:[Thymidylate synthase and dihydropyrimidine dehydrogenase activity in a metastatic liver tumor from colorectal cancer]. 1108 36

This was an open lable, pilot translational clinical pharmacology study of a brief (7 day) course of UFT, 300 mg/m2/day, in combination with leucovorin, 90 mg/day, in six patients with newly diagnosed advanced colorectal cancer. The primary objectives of the study were to examine the impact of this treatment course on the UFT targets which are thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). The rate of tumoral TS inhibition after the 7-day UFT treatment sequence varied from 5% up to 31%. UFT treatment induced a constant and variable decrease in tumor DPD activity ranging from 13% to 60%. UFT treatment induced a constant increase in uracil concentrations both in plasma and tumors. FT, 5-FU and the metabolite fluoro-beta-alanine (FBAL) were found in plasma and tumors at variable concentrations; the highest drug concentrations were those of FBAL in plasma. The present translational clinical study provides data related to the in vivo pharmacological effects of UFT with a description of its impact on cellular targets.
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PMID:Impact of UFT on tumoral TS and DPD levels in colorectal cancer. 1109 89

Although a majority of cancer patients show no response or minimal response to any given chemotherapy, all patients are nevertheless placed on standard therapy regimens because there has been no way to identify beforehand those patients who are destined not to respond. Determining the biochemical factors relevant to drug response in each patient's tumor cells prior to treatment should allow optimal therapy to be selected for each patient on a rational basis. In this paper, we summarize studies aimed at determining whether analysis of the quantitative expression levels of genes or proteins involved in cancer drug activity in clinical specimens of tumor tissue could predict the effect of the drug on a tumor. This hypothesis has been tested mostly in 5-fluorouracil (5-FU)-based regimens in colorectal cancer. In the case of 5-FU, the quantitative expression levels of thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase were found to be associated with tumor response. Using all three of these markers together resulted in very effective identification of responding patients. The salient results of these studies were that, using the PCR enhanced by newly developed methodology, gene expressions can be identified and measured in pretreatment biopsies that are quantitatively associated with either response or non-response to drugs that are used in treating colorectal cancer.
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PMID:[Molecular markers as basis for chemotherapy?]. 1119 61

The anti-cancer effect of 5-fluorouracil (5-FU) is significantly affected by the intratumoral environment. Elevated expression of thymidylate synthase (TS), the target enzyme of 5-FU, and a lack of reduced folate or FdUMP results in insufficient inhibition of TS. Further, elevated expression of DPD in the tumor tissue results in a lack of FdUMP. TS-1, which contains tegafur and dihydroxypyridine (CDHP), a potent DPD inhibitor, is a promising anticancer drug. Isovorin has been available in Japan since autumn 1999. In cancer patients, folate deficiency may be derived from increased consumption and/or absorption disturbance of folate. In such situations, sufficient TS inhibition cannot be obtained if 5-FU is administered without supplementation of reduced folate. We describe in detail the metabolism of those substances in relation to the anticancer effect of 5-FU. Further, we show the theoretical construction of first-line and second-line chemotherapy with consideration of TS and DPD expression.
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PMID:[Theoretical construction of chemotherapeutic tactics for advanced or recurrent gastrointestinal carcinoma]. 1120 82

The relationships between gene expression, protein expression, and enzymatic activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) have not been clarified in tumor and non-tumor tissues of human. In this study, we compared three different parameters by evaluating TS and DPD levels, mRNA expression assessed by RT-PCR, protein expression evaluated by immunohistochemical examination, and enzymatic activity measured by biochemical assay, in the tumor tissue and adjacent normal mucosa of 43 patients with gastrointestinal cancer. TS enzymatic activity in the tumor tissue was significantly higher than in normal tissue in both the stomach (median activity: 81.0 and 38.0 pmol/mg protein, respectively, p=0.012) and the colorectum (49.8 and 30.8, respectively, p=0.023). Similarly, TS mRNA expression in the tumor tissue was significantly higher than in normal tissue in both the stomach (median TS/GAPDH ratio: 6.0 and 2.0, respectively, p=0.009) and the colorectum (3.20 and 0.91, respectively, p=0.001). But no significant differences in DPD activity were observed between the tumor and normal tissue in either stomach (median activity: 41.3 and 41.6 pmol/min/mg protein, respectively) or colorectum (34.9 and 49.0, respectively). On the other hand, DPD mRNA levels in normal tissue were significantly higher than in tumor tissue only in the colorectum (DPD/GAPDH ratio: 0.83 and 0.20, respectively, p=0.003). No linear relationships were found between the enzymatic activity and mRNA expression of TS or DPD either in tumor or normal tissue. Nor were any correlations found between protein expression and either mRNA expression or enzymatic activity for either TS or DPD. These results suggest that tissue TS and DPD levels may vary with differences in the methods used to measure them. These discrepancies must be taken into account when interpreting correlation between TS and DPD levels and clinical outcome.
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PMID:Discrepancies between the gene expression, protein expression, and enzymatic activity of thymidylate synthase and dihydropyrimidine dehydrogenase in human gastrointestinal cancers and adjacent normal mucosa. 1125 Nov 64

5-fluorouracil (5-FU) is a widely used chemotherapeutic agent for various carcinomas. However, the therapeutic effect of 5-FU differs among patients. The differences in the effectiveness of 5-FU are thought to be based on the different enzymatic activity which inactivates 5-FU of the host tissue. 5-FU is catabolized to 2-fluoro-beta-alanine by dihydropyrimidine dehydrogenase (DPD) in liver and tumors. In this study, we investigated the clinical significance of detecting DPD activity in patients with hepatocellular and colorectal carcinomas. DPD activity in 63 hepatocellular carcinomas (HCCs), 3 cholangiocellular carcinomas (CCCs), 63 non-cancerous liver tissues adjacent to HCCs (N-HCCs), 6 normal livers (NLs), 189 colorectal carcinomas (CRCs), and 189 non-cancerous colorectal mucosas (N-CRCs) was analyzed by enzyme-linked immunosorbent assay (ELISA). The mean DPD activities of these tissues were 209 +/- 187 Unit (U)/mg protein (HCC), 140 +/- 34 (CCC), 105 +/- 50 (N-HCC), 93 +/- 24 (NL), 58 +/- 45 (CRC), and 83 +/- 92 (N-CRC). DPD activity of HCC was higher than that of CRC (p < 0.0001). DPD activity of N-HCC was higher than that of N-CRC (p < 0.0001). DPD activity of HCC was higher than that of N-HCC (p = 0.0014), on the other hand, DPD activity of CRC was lower than that of N-CRC (p < 0.0001). Tumor DPD activity in HCC and CRC did not correlate with tumor differentiation or progression nor with patient survival. In 20 CRC patients with synchronous liver metastasis, who underwent post-operative 5-FU chemotherapy through the hepatic artery, the mean survival time (29 months) of 9 patients with high DPD was not significantly different from that of 11 patients with low DPD (18 months, p = 0.3412). These findings could provide an explanation for the relative 5-FU resistance of HCC compared with CRC. However, the DPD activities of tumors may not reveal tumor differentiation or progression in HCCs or in CRCs. Moreover, the DPD activity of primary CRC may not be a good indicator of the 5-FU chemosensitivity of synchronous liver metastasis.
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PMID:Dihydropyrimidine dehydrogenase activity of cancerous and non-cancerous tissues in liver and large intestine. 1129 91

We measured pyrimidine nucleoside phosphorylase (PyNPase), a known angiogenetic factor, and dihydropyrimidine dehydrogenase (DPD) in advanced gastric cancers. PyNPase was expressed in cytoplasm of the cancer cells and surrounding interstitial cells. The levels of PyNPase and DPD were significantly higher in cancer tissue. With respect to tumor factors, the level of PyNPase was significantly higher in cases positive for venous invasion. We divided patients into two groups, with high and low activities of IAP and MMP-9. The level of PyNPase was significantly higher in the high IAP activity group. A correlation was suggested between the level of PyNPase and the activity of IAP. 5'-Deoxy-5-fluorouridine (5'-DFUR) is transformed into 5-FU by PyNPase and manifests antitumor effects. DPD is a rate-limiting enzyme in the process of degradation of 5-FU. In the present study, the level of PyNPase/DPD was significantly higher in cancer tissue. PyNPase/DPD suggests not only the malignant potential of the tumor but also the efficiency of chemotherapy using 5-FU, especially 5'-DFUR.
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PMID:[Significance of pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) in advanced gastric cancers]. 1138 13

We have investigated the correlation between the in vitro chemosensitivity to 5-FU, measured using the collagen gel droplet embedded culture drug sensitivity test (CD-DST), and the anti-tumor effect of UFT, a prodrug of 5-FU, in metastatic tumors from orthotopic implanted colon cancer in nude rats. Human colon cancer cells (KM12SM) were injected into the cecal wall of the nude rats. Five weeks later, the implanted cecal tumors were removed. Oral UFT (a daily dose of 30 mg/kg) was administered postoperatively for four weeks. After the UFT administration period, the lung and lymph nodes were analyzed macroscopically and microscopically. In vitro chemosensitivity to 5-FU in the lung and lymph node metastases was tested using CD-DST, and the enzymatic activities of thymidine synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in the lung and lymph node metastases were measured. A daily administration of UFT produced an inhibitory effect on lung metastasis compared with the control group. However, there was no difference in the frequency of lymph node metastasis. The inhibition rate produced by 5-FU in CD-DST was significantly higher for lung metastases than for lymph node metastases. There was no difference in the TS and DPD activities between the metastatic tumoral tissues. These results suggest that the organ specificity of the anti-tumor effects of UFT on colon metastases may be determined by CD-DST of 5-FU for individual tumors. The TS and DPD activity in the tumoral tissues may not affect the organ specificity of the anti-tumor effect of UFT on colon metastases.
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PMID:[Relationship between the anti-metastatic effect of UFT and in vitro chemosensitivity to 5-FU in metastatic tumors from orthotopic implanted colon cancer in nude rats]. 1138 14


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