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)

Cancer patients developing severe side effects upon chemotherapy with 5-fluorouracil (5-FU) are assumed to display reduced activity of the enzyme dihydropyrimidine dehydrogenase (DPD). Meanwhile over 20 different mutations are known in the dihydropyrimidine dehydrogenase gene (DPYD) which could be associated with a loss of enzyme function. For most of these genetic alterations, however, clear genotype-phenotype relations are still lacking. We are conducting a population study using a German cohort to determine the frequency of DPD defects in the German population and to detect new toxicity-associated mutations. Our aim is to develop a sensitive and efficient screening of tumor patients to identify patients with mutations in the DPYD gene which might be related to 5-FU-toxicity. For this purpose we analysed the whole coding region of DPYD by the technique of denaturing HPLC (DHPLC). The DHPLC analysis turned out to be a reliable method for the investigation of large samples in an acceptable cost and time range. To further elucidate the molecular basis of the DPD deficiency syndrome we will continue to analyse a patient panel receiving 5-FU.
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PMID:[Mutations in the dihydropyrimidine dehydrogenase gene and their role in 5-fluororuracil intolerance]. 1282 71

Capecitabine is an orally available fluoropyrimidine and is finally converted to 5-FU selectively in tumor tissues. In our study, we examined whether the antitumor activity of capecitabine is directly affected by a modulation of dihydropyrimidine dehydrogenase (DPD). The modulations were carried out by the overexpression of DPD in tumor cells and by tumor selective DPD inhibition. The DPD-overexpressing cells were obtained by transfection of human DPD cDNA into HCT116 human colorectal cancer cells. The HCT116 cells bearing DPD cDNA expressed about 13 times higher DPD activities than the parental HCT116 cells, and they became significantly less susceptible to capecitabine than the parental cells when transplanted into nude mice. Administration of RO0094889 that is converted to a DPD inhibitor 5-vinyluracil selectively in tumor tissues restored the antitumor activity of capecitabine against the tumor of the HCT116 cells carrying DPD cDNA and various tumors expressing DPD. As compared to 5-ethynyluracil or 5-vinyluracil, which inhibited DPD not only in tumor tissues but also in other non-cancerous tissues, the effective dose range of RO0094889 in augmenting the efficacy of capecitabine was much broader. These results indicate that the antitumor activity of capecitabine is directly affected by DPD activities in tumor tissues and therefore, the combination of capecitabine and a tumor selective DPD inhibitor, RO0094889, will be beneficial to patients who have tumors with high levels of DPD.
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PMID:Augmentation of the antitumor activity of capecitabine by a tumor selective dihydropyrimidine dehydrogenase inhibitor, RO0094889. 1286 42

To identify factors that influence the clinical response to 5-fluorouracil (5-FU), we studied the correlation between in vitro sensitivity to 5-FU and the expression of seven biological markers. The markers, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), pyrimidine nucleoside phosphorylase, p53 (wild/mutant), p21, cyclo-oxygenase-2, and inducible nitric oxide synthase were measured in tumour tissues from 32 colorectal cancer patients. The activities of TS and DPD were significantly lower in the tumours sensitive to 5-FU compared with those that were not sensitive to 5-FU. In tumours with TS < 3.7 pmol/min per mg protein and DPD < 98 pmol/min per mg protein, the percentage of cases sensitive to 5-FU (67%) and the mean percentage inhibition of tumour cells by 5-FU (42.8%) were significantly higher than in the other tumours (0% and 13.1%, respectively). The other biological markers did not correlate with in vitro sensitivity to 5-FU. Tumour sensitivity to 5-FU can be more precisely predicted by taking the activities of both TS and DPD into consideration than by using either alone.
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PMID:Intratumoural thymidylate synthase and dihydropyrimidine dehydrogenase activities are good predictors of 5-fluorouracil sensitivity in colorectal cancer. 1287 Mar 70

5-Fluorouracil (5-FU) has been used for more than 40 years in the treatment of neoplastic disease, and remains the standard first-line treatment for colorectal cancer in combination with irinotecan and leucovorin. Previous studies indicated that measurement of dihydropyrimidine dehydrogenase (DPD) gene expression before treatment was valuable in determining the potential benefit of and toxicity to 5-FU treatment. In this study, we investigated the association between intratumoral DPD gene expression and the adjacent normal tissue DPD gene expression and DPD mRNA expression level in non-paired colon tumor and normal colon tissue specimens. In addition, we have compared the difference of DPD gene expression at three different RNA concentrations from the same specimen (180, 100 and 5 ng/reaction, respectively). DPD expression was measured by quantitative RT-PCR using a LightCycler instrument in a total of 31 specimens. Gene expression values were expressed as a ratio of target gene (DPD) to the internal reference gene (G6PDH). Our study revealed no statistically significant difference (p=0.23) between tumor tissues and matched normal tissue in DPD expression. In contrast, the data on DPD mRNA expression in non-paired colon tumor and normal tissue specimens revealed a significant difference (p=0.0004) between the tumor group and the normal group. In the three RNA concentration groups, there was no significant difference (p=0.55) in gene expression at the different RNA concentrations from the same donor. These results demonstrate that intratumoral gene expression levels of DPD do not correlate with tumor cell percentage or with RNA concentration. Thus, DPD mRNA expression appears to be a valid sensitivity test for 5-FU in spite of a varying density of tumor cells and RNA yield in specimens submitted for analysis.
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PMID:Quantitation of dihydropyrimidine dehydrogenase (DPD) mRNA expression levels in normal colon and colorectal cancer tumor paraffin-embedded tissue specimens. 1296 Jul 41

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) has been suggested to be sensitivity-limiting factors of 5-fluorouracil therapy in cancer patients. We conducted a large-scale population study on the activity of TS and DPD in patients with various solid tumors. A total of 2590 clinically removed tumors, consisting of 1112 colon, 724 gastric, 520 breast, and 236 non-small cell lung cancers, were provided to measure TS and DPD activity. TS activity in the gastric, colon, and non-small cell lung cancers was significantly higher than in matched non-cancerous tissue (P<0.0002), but there was no difference in TS expression between tumor and non-cancerous tissue from breast cancer patients. Gastric, breast, and non-small cell lung cancers showed significantly higher DPD activity than their corresponding non-cancerous tissues, but colon cancers did not. There was no correlation between TS activity and DPD activity, and thus each enzyme was considered to be an independent sensitivity-limiting factor for 5-fluorouracil therapy. The median TS activity and median DPD activity in all specimens including gastric, colorectal, breast, and non-small cell lung cancers tested were 0.041 and 110.1 pmol/mg protein, respectively. We classified each of the type of carcinoma into 4 groups by using the median activity of TS and DPD as the cutoff values: a low TS/low DPD group, high TS/low DPD group, low TS/high DPD group, and high TS/high DPD group. About 50% of the gastric, 47% of the colon, 70% of the breast and 30% of the non-small cell lung cancers had high TS activity, and 60% of the gastric, 40% of the colon, 48% of the breast, and 87% of the lung cancers had high DPD activity. Moreover, breast cancer was characterized by high TS activity and lung cancer by high DPD activity as compared with gastric and colon cancers, and their high activity levels may influence to the effectiveness of 5-fluorouracil against cancers of these organs. The results for expression of TS and DPD in clinically dissected tumors would be useful to estimate the efficacy of 5-fluorouracil in the treatment of cancer patients.
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PMID:Population study of expression of thymidylate synthase and dihydropyrimidine dehydrogenase in patients with solid tumors. 1461 54

Pyrimidine nucleoside phosphorylase (PyNPase) converts 5'-deoxy-5-fluorouridine to 5'-fluorouracil, which exerts an anticancer effect before being catabolized by dihydropyrimidine dehydrogenase (DPD). Recently, PyNPase has been shown to be identical to a potent angiogenic factor, platelet-derived endothelial cell growth factor. We analyzed the concentration of PyNPase and DPD in 33 patients with esophageal squamous cell carcinoma in fresh-frozen samples by enzyme-linked immunosorbent assay. In addition, we evaluated the clinical significance and prognostic value of PyNPase expression in esophageal carcinoma. The PyNPase concentration of tumor tissue was statistically higher than that of normal tissue of the esophagus (248 +/- 146 U/mg protein vs 73 +/- 63 U/mg protein, P = 0.0001), whereas DPD showed no difference (90 +/- 62 U/mg protein vs 88 +/- 62 U/mg protein, P = 0.825). The ratio of PyNPase to DPD of tumor tissue was statistically higher than that of normal tissue of the esophagus (3.3 vs 0.95, P = 0.0001). There were no significant differences between the group with high tumor to normal tissue ratios of PyNPase concentration and the low-ratio group in terms of the tumor length, depth, lymph node metastasis, lymph vessel invasion, vascular invasion, stage and survival. In conclusion, 5'-deoxy-5-fluorouridine may be effective on esophageal carcinoma and PyNPase concentration in esophageal carcinoma may not be a useful prognostic marker for patients with esophageal squamous cell carcinoma.
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PMID:High level concentration of pyrimidine nucleoside phosphorylase in esophageal squamous cell carcinoma but no correlation with clinicopathological parameters. 1464 Dec 94

The skeleton is the most frequent site of metastatic disease in breast cancer and also the site of greatest morbidity. In addition, there is now recognition that accelerated bone loss associated with chemotherapy or hormonal therapy leads to an increased risk of osteoporosis in long-term breast cancer survivors. An improved range of treatment options is available and assessment of skeletal response both to the disease and to therapy is therefore of growing importance. Plain radiographs remain widely used to assess response, but are of limited sensitivity. The isotope bone scan is more sensitive, but lacks specificity. Computerised tomography, magnetic resonance imaging and positron emission tomography all have an increasing role. In treatment-induced osteoporosis, bone mineral density is now readily measured by DEXA scanning. Tumour markers such as CEA, CA 15-3, CA 549 and TPA may have a role in assessing response, but probably in combination rather than individually, using an appropriate quantitative model. Several trials have shown that bone markers, especially markers of bone resorption such as Ntx, Ctx, PYD and DPD, appear to have strong potential as rapid, convenient and inexpensive measures of response. There is also evidence that they may be used as predictive or prognostic indicators. Evidence is accumulating that the reduction of bone resorption markers into the normal range results in substantially reduced morbidity in metastatic breast cancer and that this should be a major target of therapy.
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PMID:Assessment of the effects of breast cancer on bone and the response to therapy. 1496 99

We measured TS and DPD activities in 40 patients with colorectal cancer who had undergone surgical reduction in our department between May 1997 and April 1998, including 26 patients with preoperative UFT (450 mg/body/day) chemotherapy for 2 weeks, and evaluated the clinical significance of TS and DPD activities as predictive factors of UFT sensitivity. TS activity was collated with histological type from a clinical pathological examination (p = 0.0103). Also, the tendency for TS activity to become high with the stage was observed. According to the evaluation of pathological response, histological effectiveness greater than grade 2 was noted in 7.7%. The apoptosis index (AI) in tumors with preoperative UFT chemotherapy was higher than those without such treatment, which showed a higher correlation with DPD activity of tumor tissue than TS activity (p = 0.0465). Recurrence was seen in 7 cases (lung metastasis: 2, liver metastasis: 4, and local recurrence: 1) in the preoperative chemotherapy group. TS activity was high in all patients with recurrence. TS showed significantly high activity in patients with recurrence compared with the non-recurrence (p = 0.0034) patients. Therefore, these results suggested that activity of both TS and DPD was a key factor for anti-tumor effectiveness of UFT. In particular, TS activity was an important predictive factor for effectiveness of UFT in recurrences.
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PMID:[Clinical significance of TS and DPD activities in colorectal carcinoma as a predictive factor of UFT sensitivity]. 1499 49

A 48-year-old woman presented with a tumor in the supra-clavicular fossa. Under a diagnosis of advanced ileocecal colon cancer with metastases to Virchow's and the paraaortic lymph nodes, ileocecal resection was performed. After surgery, the patient was given 5-FU infused continuously at 500 mg/body per day, and levofolinate was dripped intravenously at 100 mg/body over 2 hours for 5 successive days per week. Two cycles were repeated each week. She was then intravenously given weekly modulation chemotherapy consisting of 125 mg/body levofolinate and 500 mg/body of 5-FU for about 5 months on an outpatient basis. Furthermore, the same administration schedule was continued bi-weekly for 1 year and 4 months. As a result, the enlarged paraaortic lymph nodes had completely disappeared by 5 months after administration of levofolinate.5-FU. The Virchow's lymph node metastasis has not been palpable for 11 months. Throughout the period of treatment, there were no severe side effects and as of this writing, no sign of recurrence for 3 years after surgery. A high quality of life has been maintained. In conclusion, this case seems significant from the viewpoint of the complete long-term response to a moderate dose of levofolinate.5-FU therapy and the long duration of administration, which was tolerable with few side effects. Moreover, we identified the presence of TS and DPD using immunohistochemical staining techniques, when both primary tumor and regional lymph nodes were all negative for the stain test. It was suggested that this cancer especially would responded to 5-FU chemotherapy.
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PMID:[A case of advanced colon cancer with metastases to both the Virchow's and the paraaortic lymph nodes that achieved complete long-term response with levofolinate.5-FU therapy]. 1504 54

Thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are considered to be key enzymes affecting the prognosis for patients with gastric and colorectal cancers. We tried to prove the correlation of TP and DPD expressions in gastric and colorectal cancers. The present study was designed to quantify TP and DPD levels by an enzyme-linked immunosorbent assay (ELISA) in tumors and normal tissues obtained from 16 gastric and 20 colorectal cancer patients. TP and TP/DPD ratio in the tumor specimens were almost all higher than those in each normal tissue, especially for tumors in the progressive state. In the early stage of the colorectal cancer group, DPD in the normal tissues were higher than those in the tumor specimens. There were no significant differences between TP levels in the tumor specimens of the two groups, whereas in stages III and IV, those of the gastric cancer group tended to be higher than those of colorectal cancer group. In stages I and II, DPD levels in the tumor specimens tended to be higher in the gastric cancer group than in the colorectal cancer group. DPD T/N was higher in the gastric cancer group than in the colorectal cancer group. There were no significant differences between TP/DPD ratios in the tumor specimens of the two groups, whereas those in normal tissue were higher in the gastric cancer group than in the colorectal cancer group. We may be able to achieve the successful effects or reduction of side effects of anticancer chemotherapy for gastric and colorectal cancer using the results of this study.
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PMID:Comparative analysis of thymidine phosphorylase and dihydropyrimidine dehydrogenase expression in gastric and colorectal cancers. 1506 45


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