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)

Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an inactivator of dihydropyrimidine dehydrogenase, enabling catabolite correction and calculation of tissue pharmacokinetic parameters to be achieved. Using this novel approach, we report for the first time that the net clearance of 5-[(18)F]FU from plasma into tumors (liver metastases and pancreatic tumor) of patients is low (K(I) = 0.0033 +/- 0.0005 ml plasma/ml tissue/min). In contrast, the initial (up to 10 min) clearance through catabolism in liver was high (K(I) = 0.7313 +/- 0.092 ml plasma/ml tissue/min). In the absence of eniluracil, catabolites in tumors accounted for 83% of total tumor exposure (range, 66-91%), whereas catabolites in liver accounted for 96% of total liver exposure (range, 94-98%). This study provides definitive evidence that the cytotoxicity of 5-FU in patients with gastrointestinal cancer could be compromised by its intrinsically low uptake by tumors, as well as decreased systemic availability through hepatic catabolism.
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PMID:Extraction of 5-fluorouracil by tumor and liver: a noninvasive positron emission tomography study of patients with gastrointestinal cancer. 1143 19

In the recent studies associated with the modulation of 5-fluorouracil (5-FU) and the development of new antifolates, attentions have been focused on the expression of the target enzymes, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD), that affect tumor sensitivity and resistance to drugs. In order to evaluate predictability of therapeutic efficacy by intratumoral enzyme activity, we investigated the role of TS content and DPD activity in tumor sensitivity of 5-FU. Surgical specimens were obtained from 51 patients with colorectal cancer and used to measure TS content and DPD activity. TS content and DPD activity in tissues were measured by [3H]-FdUMP binding assay and radioenzymatic assay, respectively. The sensitivity to 5-FU in tumor specimens was determined by collagen-gel droplet embedded-drug sensitivity test (CD-DST). The TS content and DPD activity did not correlate with Dukes' staging. There was no correlation between TS content and DPD activity in any tumors. Simple linear regression analysis showed that neither DPD activity (r = -0.267, p > 0.05) nor TS content (r = -0.277, p > 0.05) in tumors had a significant correlation with 5-FU effectiveness independently. Four out of 24 patients, highly responsive to 5-FU, showed low levels in both DPD and TS. The patients with high value in either DPD activity or TS content proved not to respond to 5-FU. In conclusion, these results demonstrate that both tumor DPD activity and TS content are the factors predicting 5-FU responsiveness in colorectal cancer.
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PMID:Dihydropyrimidine dehydrogenase activity and thymidylate synthase level are associated with response to 5-fluorouracil in human colorectal cancer. 1150 4

Deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-fluorouracil (5-FU) catabolism, has been linked to toxic side effects of 5-FU. The most prominent mutation of the DPD gene resulting in severe DPD deficiency is a G to A mutation in the GT 5'-splice recognition site of intron 14 (exon 14-skipping mutation). The corresponding mRNA lacks exon 14, and the enzymatic activity of the translated DPD protein is virtually absent. We developed a reverse transcription-PCR-based assay suitable for routine identification of the exon 14-skipping mutation and screened a control cohort of 851 Caucasian individuals as well as a cohort of 25 cancer patients reported by their physicians to have suffered from WHO grades 3-4 toxicity upon 5-FU chemotherapy. Within the control cohort, in total, eight heterozygotes were detected (0.94%): one heterozygote in 51 healthy donors, (1.96%); five heterozygotes in 572 hospital patients (0.87%); and two heterozygotes in 228 colorectal tumor patients (0.88%). Among the 25 patients with severe 5-FU-related toxicity, 5 (20%) were heterozygous and 1 (4%) was homozygous for the exon 14-skipping mutation. All six patients had experienced WHO grade 4 myelosuppression. Lethal outcome was seen in the homozygous and two of the heterozygous cases. We conclude that carriers of the DPD exon 14-skipping mutation are at significantly increased risk to experience life-threatening myelosuppression upon 5-FU treatment, even when the allelic status is heterozygous. These data lead us to suggest routine testing for the exon 14-skipping mutation before 5-FU treatment.
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PMID:Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. 1200 55

In sera of cachectic patients bearing advanced cancers, the concentration of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrotizing factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) have been reported to elevate. In this study, we investigated whether those cytokines influenced in vitro anti-tumor effect of 5-fluorouracil (5-FU) on a human colon tumor cell line, HCT-15. Pretreatment of HCT-15 cells with IL-1 beta, IL-6 or TNF-alpha did not affect the anti-tumor effect of 5-FU at various concentrations. However, IFN-gamma attenuated the anti-tumor effect of 5-FU at the concentrations of 0.1-10 IU/ml. An experiment with tritium thymidine showed that 0.1 IU/ml of IFN-gamma did not suppress the growth of HCT-15 cells. As low as 0.1 IU/ml of IFN-gamma attenuated the anti-tumor effect of 5-FU in another experimental system where HCT-15 cells were exposed to 0.1 IU/ml of IFN-gamma before and during the treatment with 5-FU. This system mimicked the clinical condition around in situ cancer cells. Treatment of HCT-15 cells with 0.1-10 IU/ml of IFN-gamma did not change their DNA histogram pattern. An immunoblotting with the antibodies to thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in HCT-15 cells revealed that 0.1-10 IU/ml of IFN-gamma enhanced their TS and DPD expressions. Results of the immunoblotting gave some explanation to attenuation in the sensitivity of HCT-15 cells to 5-FU.
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PMID:Serum factors attenuating the anti-tumor activity of 5-fluorouracil. 1160 2

The measurement of the intra-tumoral level of thymidylate synthetase (TS), and dihydropyrimidine dehydrogenase (DPD), may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). In this study, we examined the mRNA levels of DPD and TS in 28 oral squamous cell carcinomas (SCC), and 22 salivary gland tumors by semi-quantitative reverse transcription polymerase chain reaction. Then we examined the correlation of the responsiveness of the patients with oral SCC to 5-FU with the intra-tumoral levels of DPD and TS mRNA. All specimens were obtained at the biopsy before treatment, and then the patients were treated by oral administration of a 5-FU compound (UFT), the irradiation of cobalt-60 (upto 60 Gy) and injection of an immuno-potentiator (OK-432). Intra-tumoral levels of DPD mRNA in the patients who showed CR (complete response) and PR (partial response) were significantly lower than those in the patients who showed NC (no change). However, intra-tumoral levels of DPD mRNA did not correlate with the local recurrence of the tumor during the observation period after initial treatment with or without surgical resection of the residual tumors. On the other hand, TS mRNA levels in the tumors did not correlate with any clinico-pathological parameters. These observations suggest that intra-tumoral levels of DPD mRNA may predict the tumor response to 5-FU-based chemo-immuno-radiation therapy in the patients with oral SCC.
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PMID:Dihydropyrimidine dehydrogenase mRNA level correlates with the response to 5-fluorouracil-based chemo-immuno-radiation therapy in human oral squamous cell cancer. 1160 93

We evaluated the usefulness of the following three in vitro assays in cases of resected colorectal liver metastases. Chemosensitivity by collagen gel droplet drug sensitivity test (CD-DST) was very low in all cases, suggesting this method is not predictive for this disease. In contrast, thymidylate synthetase (TS) activity and dihydropyrimidine dehydrogenase (DPD) activity in tumor tissue were high in many patients with recurrent disease. Thus, these enzyme activities are promising for assessment of clinical outcome following hepatic resection of colorectal liver metastases. Further analyses with large numbers of cases are needed to determine the significance of these in vitro studies.
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PMID:[Evaluation of chemosensitivity testing by CD-DST, and TS and DPD activity in cases of colorectal liver]. 1170 70

We studied whether the immunohistochemical status of dihydropyrimidine dehydrogenase (DPD) and p53 can be used to predict the sensitivity to chemoradiotherapy (CRT) in patients with esophageal cancer. In 19 patients who did not undergo preoperative CRT, the immunoreactivity of DPD and p53 in biopsied specimens correlated well with those in surgically resected specimens (DPD: 100%, p53: 73%). Fifteen patients were treated with 5-FU (250-300 mg/body/day: day 1-5, 8-12), low-dose cisplatin (10 mg/body/day: day 1, 8) and radiotherapy (30-40 Gy). The response rate (CR + PR) for CRT in these patients was 40%. All tumors that showed CR or PR demonstrated low expression of DPD. However, all tumors with high DPD expression showed MR or NC. However, the expression of p53 did not correlate with the response rate for CRT. Therefore, the effect of CRT for esophageal cancer may be predicted by immunohistochemical examination of DPD in biopsied tumor specimens.
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PMID:[Immunohistochemical study of dihydropyrimidine dehydrogenase (DPD) and p53 in biopsied specimens of esophageal cancer before chemoradiotherapy]. 1170 71

We examined enzymatic activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in non-small cell lung cancer (NSCLC) tissues to determine the relationship to tumor sensitivity to 5-fluorouracil (5-FU). TS and DPD activities were measured in 60 surgically resected primary NSCLC tissues using a TS-binding assay and a radioenzyme assay, respectively. In vitro tumor sensitivity to 5-FU was assayed using a collagen gel droplet embedded culture drug test (CD-DST). DPD activities slightly correlated with in vitro sensitivity to 5-FU (r=0.402,P=0.013), such that tumors with higher DPD activity were more resistant to 5-FU. In contrast, no correlation was observed in TS activities. Thus, it was suggested that only DPD activity in NSCLC tissues is a potential indicator in predicting tumor sensitivity to 5-FU. Based on these results, further study is needed to evaluate the clinical significance of these enzymes in 5-FU-based chemotherapy for patients with NSCLC.
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PMID:Thymidylate synthase and dihydropyrimidine dehydrogenase activities in non-small cell lung cancer tissues: relationship with in vitro sensitivity to 5-fluorouracil. 1171 38

We measured the dihydropyrimidine dehydrogenase (DPD) activity considered to regulate the sensitivity of pyrimidine fluoride anti-cancer drugs in 50 cases of urothelial cancer (preoperative therapy group 10 cases, non-therapy group 40 cases). The association of DPD activity with pathological factors and TS activity as well as the influence of UFT oral administration on the DPD activity in tumors and blood were studied. The DPD activity in cancer tissue tended to be higher than that in the mucous membranes of the non-tumor region, but the difference was not significant. The DPD activity was high in infiltrative cancer (p < 0.05) but was not associated with atypia. The TS activity and DPD activity were manifested independently. The DPD activity in cancer tissue was significantly higher after UFT administration, with levels of 76.7 +/- 71.0 pmol/mg/min before administration and 220.6 +/- 129.1 pmol/mg/min after (p < 0.05). The DPD activity in peripheral blood was elevated after administration, but no significant difference was found. Since DPD activity is found in urothelial cancer tissue, 5-FU stable to DPD should preferably be used. It is also suggested that using a more potent DPD inhibitor in combination will produce higher anti-tumor effects.
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PMID:[Dihydropyrimidine dehydrogenase activity in urothelial cancer--influence of UFT administration on DPD activity]. 1172 80

We have assessed pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) activity to compare the chemosensitivity of 5-fluorouracil (5-FU) and doxifluridine (5'-DFUR). Tumor samples were prepared from fresh surgical specimens of 28 patients with advanced colon carcinoma. The activity levels of the two enzymes were assessed as indicators of chemosensitivity to 5'-DFUR and 5-FU. PyNPase activity was analyzed using the HPLC method, and DPD activity was assessed according to the methods of Naguib et al. (1985). A histoculture drug response assay (HDRA) was conducted according to the methods described by Furukawa et al. (1992). The mean and standard deviation of PyNPase activity in the tumor tissue was 110 +/- 48.6 &mgr;g 5-FU/mg protein/h, which was statistically higher than the corresponding value obtained in normal tissue (60 +/- 43.1 &mgr;g 5-FU/mg protein/h) (P < 0.005). When chemosensitivity to the two drug forms was compared in 16 samples obtained from 16 cases with colon cancer, 1 specimen was sensitive to both drug forms, 3 specimens were exclusively sensitive to 5'-DFUR, 5 specimens were exclusively sensitive to 5-FU, and the other 7 specimens were insensitive to both drugs, without significance. High PyNPase activity was associated with a high chemosensitivity to 5'-DFUR, and high DPD activity correlated with a low chemosensitivity to 5-FU. However, the converse relationship was not found. We suggest that the activity of PyNPase and DPD represents a reliable indicator for the chemosensitivity of colon cancer to 5'-DFUR and 5-FU, respectively.
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PMID:Pyrimidine nucleoside phosphorylase and dihydropyrimidine dehydrogenase indicate chemosensitivity of human colon cancer specimens to doxifluridine and 5-fluorouracil, respectively. 1181 May 6


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