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)

Biochemical modulation of 5-fluorouracil (5-FU) has been used over the past 20 years to improve the therapeutic efficacy of this antineoplastic agent. Recently, modulation of the catabolic pathway of this fluoropyrimidine has been the focus of extensive preclinical and clinical investigation. Dihydropyrimidine dehydrogenase catalyzes the rate-limiting step in the catabolism of 5-FU and rapidly degrades 60-90% of the drug. An irreversible inactivating inhibitor of this enzyme, 5-ethynyluracil (EU), markedly improves the antitumor effect of 5-FU in animal models. Early clinical studies have shown a substantial alteration of the systemic disposition of 5-FU with an increase in 5-FU terminal half-life and have also indicated that EU allows safe oral administration of 5-FU by improving the oral bioavailability of the fluoropyrimidine, which is otherwise too erratic and unpredictable for a drug with such a limited therapeutic window. We evaluated the effect of EU on the metabolism of 5-FU in mice bearing colon 38 tumors using 19F nuclear magnetic resonance spectroscopy. Ex vivo measurements of tissue extracts from liver, kidney, and tumor indicated a >95% elimination of alpha-fluoro-beta-ureidopropionic acid and a-fluoro-beta-alanine signals in the tissues of mice that received 2 mg/kg of EU before administration of 5-FU. The spectra also showed an increased formation of fluoronucleotides in both normal and tumor tissues, a prolonged presence of 5-FU, and the accumulation of 5-fluorouridine that otherwise is undetectable, particularly in normal tissues. The in vivo NMR experiments on colon 38 tumors confirmed these findings, showing a complete elimination of the a-fluoro-beta-ureidopropionic acid and a-fluoro-beta-alanine signals in tumors treated with EU and a dramatic formation and accumulation of 5-fluorouridine mono-, di-, and triphosphates and 5-fluorouridine. Thus, by inactivating dihydropyrimidine dehydrogenase, EU prolonged the half-life for 5-FU, almost completely eliminated its catabolism for 4-6 h, which led to an increased accumulation of 5-fluorouridine mono-, di-, and triphosphates in both normal and tumor tissues.
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PMID:In vivo effect of 5-ethynyluracil on 5-fluorouracil metabolism determined by 19F nuclear magnetic resonance spectroscopy. 989 96

Protein levels and gene expression of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme for degradation of 5-fluorouracil, were studied in two human tumor cell lines (fibrosarcoma HT-1080 and pancreatic carcinoma MIAPaCa-2) in various growth phases of the cultured cells and of tumor xenografts implanted into nude mice. DPD catalytic activity and DPD protein content in cytosolic preparations were determined by means of radioenzymatic assay and western blot analysis, respectively. Relative DPD mRNA expression was determined by using a semi-quantitative reverse transcription-polymerase chain reaction in which glyceraldehyde-3-phosphate dehydrogenase mRNA was used as an internal standard. DPD activity and protein content in cultures of both cell lines increased in proportion to cell density (DPD activities ranged from undetectable to 84 pmol/min/mg protein in the HT-1080 cells and from undetectable to 335 pmol/min/mg protein in the MIAPaCa-2 cells). DPD mRNA levels, on the other hand, tended to decrease slightly during cell growth. DPD activity and protein content in HT-1080 tumor xenografts increased during growth in proportion to tumor weight (DPD activities ranged from 7 to 131 pmol/min/mg protein), but DPD mRNA levels did not correlate with tumor weight. DPD activity and protein content in MIAPaCa-2 tumor xenografts did not change much, and seemed to have already plateaued, since the tumors were small (weighing about 30 mg). These findings suggest that DPD protein expression during tumor growth is controlled at the post-transcriptional level.
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PMID:Relationship between protein levels and gene expression of dihydropyrimidine dehydrogenase in human tumor cells during growth in culture and in nude mice. 991 83

In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra) against colorectal cancer, S-1, a combination agent including a prodrug of FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, and potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribosylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinically relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fold higher than that of either FT or FUra. S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FUra and FT, were not observed with S-1. In an attempt to understand the basis for the observed superior therapeutic selectivity with S-1, we studied pharmacokinetic analysis of FUra, drug-induced apoptosis, suppression of mitosis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT administration. The peak plasma FUra concentrations derived from FUra or S-1 (FT) at comparable MTDs were similar, but the plasma level of FUra was higher with S-1 than with FUra. Induction of high and sustained apoptosis was achieved with S-1. Although the initial level of apoptosis induced by FUra was comparable to S-1, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition. Mitotic figures were more greatly suppressed with S-1 treatment than with FUra. Studies on TS inhibition indicated that, although both S-1 and FUra caused a 4- to 6-fold induction of total TS protein, single oral administration of S-1 was superior to 24-h infusion of FUra in suppressing free TS. The data are consistent with the observation that the therapeutic efficacy of S-1 (100% cure) over FUra is associated with high and sustained levels of drug-induced apoptosis, greater suppression of mitosis, and inhibition of free TS in tumor tissues.
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PMID:Persistent induction of apoptosis and suppression of mitosis as the basis for curative therapy with S-1, an oral 5-fluorouracil prodrug in a colorectal tumor model. 1003 74

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and the enzymatic activity and mRNA levels of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) using human tumor xenografts in nude mice. Three gastric carcinoma xenografts (SC-1-NU, St-4, and H-111), two colon carcinoma xenografts (Co-4 and Col-3-JCK), one pancreatic carcinoma xenograft (PAN-3-JCK), and one breast carcinoma xenograft (MX-1) were inoculated into nude mice. When the resultant tumors reached 100-300 mg, 5-FU was administered i.p. at a dose of 60 mg/kg in a schedule of three times every 4 days, and the antitumor activity of 5-FU was evaluated as the relative mean tumor weight in treated mice compared to control mice. Xenografts were also inoculated into untreated nude mice. When tumors weighed 200-300 mg, tumor tissues were resected for measurement of tumoral TS and DPD. TS and DPD activities were detected by the TS-binding assay and a radioenzymatic assay, respectively. mRNA levels were measured by semiquantitative reverse transcription-PCR, with glyceraldehyde-3-phosphate dehydrogenase coamplified as an internal standard. TS and DPD activities ranged from 84.7 to 775.5 fmol/mg protein and from not detectable to 79.7 pmol/min/mg protein, respectively. TS and DPD mRNA levels ranged from 0.51 to 9.90 and from not detectable to 0.93, respectively. The enzymatic activities of TS and DPD were correlated with observed mRNA levels. DPD levels were significantly correlated with 5-FU sensitivity, with high DPD activity and high DPD mRNA level resulting in low sensitivity to 5-FU. In contrast, no correlation between TS level and 5-FU sensitivity was observed. Tumoral DPD activity and DPD mRNA level may be useful indicators in predicting the antitumor activity of 5-FU.
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PMID:Dihydropyrimidine dehydrogenase activity and messenger RNA level may be related to the antitumor effect of 5-fluorouracil on human tumor xenografts in nude mice. 1021 25

We report a case in which UFT was effective as a preoperative treatment for stage II b cervical cancer. The patient was a 66-year-old female whose chief complaint was brown vaginal discharge. Following cytological, histological and CT examinations, a diagnosis was made of papillary squamous cell carcinoma invading the vagina and left parametrium. We administered UFT (600 mg/day, for 5 days) as one course, and conducted two courses with an interval of 2 days. The tumor had shrunk 2 weeks later and a radical hysterectomy was performed after additional treatment with intraarterial cisplatin (120 mg/body) infusion. Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD), which are enzymes in 5-FU metabolism, and the labeling index (ID) of DNA fragmentation in the tumor were estimated before and after UFT. The results showed that TS was 0.69 pmol/g tissue and DPD 39.98 pmol/mg/min before UFT, and that LI of DNA fragmentation was 21.8 +/- 5.0% before UFT and 37.9 +/- 16.2% after UFT. We suggest that preoperative UFT administration is an effective treatment for cervical cancer, and that TS, DPD and LI of DNA fragmentation might be useful biomarkers to estimate the sensitivity of UFT.
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PMID:[A case of uterine cervical cancer in which UFT was an effective preoperative treatment]. 1058 79

Several recent studies have reported a correlation between intratumor dihydropyrimidine dehydrogenase (DPD) messenger RNA (mRNA) levels and sensitivity to 5-fluorouracil (5-FU). However, significant tissue requirements and labor-intensive methodology have limited the large-scale studies necessary for statistical validation. In addition, the semiquantitative results obtained by these methods further limit their application. We have developed a real-time reverse transcription-PCR (RT-PCR) assay, based on TaqMan fluorescence methodology, capable of rapid and accurate quantitation of DPD mRNA levels in biopsy-sized tissue samples. Results obtained with this approach indicate a linear dynamic range of 10(8)-10(3) DPD mRNA copies, with an intra-assay variation of <5%. We evaluated the data using three different methods (absolute standard curve, relative standard curve, and comparative C(T)) and show them to be equivalent. This RT-PCR assay was validated by quantitative comparison to Northern blot analysis in five tissues. In addition, analysis of 18 colorectal tumor and liver tissue specimens demonstrated a significant correlation (r(2) = 0.90) between DPD enzyme activity and mRNA levels. This method provides the first high-throughput, reproducible, and sensitive technique capable of determining DPD mRNA expression levels in nanogram amounts of total RNA.
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PMID:Quantitation of dihydropyrimidine dehydrogenase expression by real-time reverse transcription polymerase chain reaction. 1066 Apr 60

Pharmacogenetics has emerged as a novel and challenging area of interest in oncology. Cancer chemotherapy is characterized by major intersubject variability in tumor responses and host toxicity. This variation may be caused by genetic differences in the enzymes involved in the metabolism of anticancer agents. Anticancer agents, such as 6-mercaptopurine, 5-fluorouracil, and irinotecan, have a narrow therapeutic index that can sometimes result in severe life-threatening toxicities. The impact of polymorphisms in metabolizing enzymes (thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, and uridine diphosphate glucuronosyltransferase) that participate significantly in the disposition of these anticancer agents is discussed.
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PMID:Inherited variations in drug-metabolizing enzymes: significance in clinical oncology. 1067 43

The measurement of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) enzymatic activities and mRNA levels in tumors may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in this study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD mRNA levels. We also measured TS and DPD enzymatic activities and mRNA levels in surgically resected gastric cancer samples, as well as in adjacent normal gastric mucosa. TS and DPD activities were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-PCR (RT-PCR) co-amplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. In resected tumor specimens, TS and DPD activities ranged from 7.1 to 176.6 fmol/mg protein and from 3.6 to 99.8 pmol/min/mg protein, respectively, while TS and DPD mRNA levels ranged from 0.50 to 21.12 and from 0.014 to 7:22, respectively. There were no significant correlations between TS/DPD levels and other clinicopathological factors, except for low DPD mRNA levels in undifferentiated carcinoma. Both TS activity and mRNA levels were significantly higher in tumor tissues compared to normal adjacent mucosa. In contrast, there was no significant difference between tumoral and non-tumoral DPD activity, although tumor tissue showed significantly lower DPD mRNA levels than non-tumoral tissue. High tumoral TS mRNA levels in preoperative biopsy specimens from patients with stage III/IV was associated with poor survival outcome after surgery compared with patients with low tumoral TS mRNA levels. In contrast, DPD levels had no influence on prognosis. We conclude that high tumoral TS levels and low tumoral DPD mRNA may indicate the selective cytotoxicity of 5-FU on gastric cancer, and that tumoral TS mRNA levels may be a prognostic factor for patients with stage III/IV gastric cancer.
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PMID:Thymidylate synthetase and dihydropyrimidine dehydrogenase levels in gastric cancer. 1069 32

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and enzymatic activities of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in the study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels. TS and DPD enzyme activity and mRNA levels were also measured in resected tumor tissue samples obtained after surgical resection. TS and DPD activity were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), with co-amplification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. 5-FU sensitivity of resected tumor specimens was measured by the tetrazolium-based colorimetric assay (MTT assay). Both TS and DPD mRNA levels correlated well between biopsied and resected tumor specimens. A statistically significant correlation was also observed between mRNA levels in biopsied specimens and enzymatic activities in resected specimens. DPD levels significantly correlated with 5-FU sensitivity, such that high DPD activity and high DPD mRNA levels resulted in low sensitivity to 5-FU. In contrast, no correlation was observed between TS activity or TS mRNA levels and 5-FU sensitivity. We conclude that tumor DPD mRNA level, as assessed from biopsy specimens obtained by gastrofiberscopy, may be a useful indicator in predicting tumor sensitivity to 5-FU in patients with gastric cancer.
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PMID:Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: possible predictor for sensitivity to 5-fluorouracil. 1074 51

Advanced tumor osteopathy is characterized by abnormal bone turnover. Using a rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis, the aim of the present study was to define the sequential changes in, and the association between, biochemical and histomorphometric indices of bone metabolism during the early stages of developing tumor osteopathy. Eight-month-old Wistar rats (n = 48) were subcutaneously inoculated with either 2 x 10(6) cells of the Walker carcinosarcoma 256, or saline on day 0, and treated with either saline or the bisphosphonate ibandronate until killing on day 8. Serum calcium (sCa), alkaline phosphatase (sTAP), and osteocalcin (sOC) and urinary calcium (uCa), deoxypyridinoline (uDPD), and pyridinoline (uPYD) were measured daily. In a second semilongitudinal experiment (n = 70), the number of osteoclasts and osteoblasts (N.Oc, N.Ob), trabecular bone volume (BV/TV), and osteoid volume (O.Ar) were assessed by histomorphometry. In untreated tumor-bearing animals, osteoclast numbers increased by 74% on day 3 (5.4 +/- 2.4 vs. 3.1 +/- 1.5/mm(2), p < 0.05), and trabecular bone volume fell by 24% on day 4 (12.5 +/- 2.0 vs. 15.8 +/- 1.2%, p < 0.05). Both time course and magnitude of these changes were closely reflected by an increase in uDPD (0.46 +/- 0.14 vs. 0. 31 +/- 0.15 nmol/12 h, p < 0.05) and uPYD on day 4 (1.44 +/- 0.25 vs. 1.03 +/- 0.3 nmol/12 h, p < 0.05), sCa (3.8 +/- 0.52 vs. 3.0 +/- 0. 13 mmol/L, p < 0.01), and uCa (0.13 +/- 0.08 vs. 0.03 +/- 0.01 mmol/12 h, p < 0.001) on day 6, and sTAP (254 +/- 127 vs. 120 +/- 40 U/L, p < 0.001) on day 7 (mean +/- SD), whereas sOC remained unchanged until day 8. When combining the results of the two experiments, a high correlation was found between the number of osteoclasts and the urinary excretion of PYD (r = 0.91) and DPD (r = 0.89). Treatment with ibandronate delayed hypercalcemia, abolished hypercalciuria, and accelerated bone resorption. We conclude that osteoclast activation is an early event in PTHrP-mediated osteolysis, which is closely reflected by the renal excretion of pyridinium cross-links of type I collagen. Therefore, specific biochemical markers of collagen breakdown may be useful as early indicators of developing tumor osteopathy.
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PMID:Association between histomorphometry and biochemical markers of bone turnover in a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis. 1077 87


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