Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regional infusion with fluoropyrimidines is useful in the treatment of hepatic metastases. However, the effectiveness of regional infusion is minimized by rapid degradation of 5-fluorouracil (FUra) and 5-fluoro-2'-deoxyuridine (FdUrd) by the liver which limits the availability of drug for anabolism to active metabolites. 5-Benzyloxybenzyluracil (BBU) is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), the initial enzyme in FUra catabolism (Naguib FMN, el Kouni MH and Cha S, Biochem Pharmacol 38: 1471-1480, 1989). The effect of BBU on fluoropyrimidine catabolism in the liver was evaluated using the isolated perfused rat liver (IPRL). BBU infused at 0.35 microM over the course of 1 hr demonstrated no hepatotoxicity as measured by bile flow, O2 uptake and lactate dehydrogenase leakage. The effect of BBU (0.35 microM) on the catabolism of FUra (10 microM) or FdUrd (10 microM) was quantitated by HPLC at 5- or 10-min intervals over a 1-hr period. BBU maximally inhibited FUra catabolism by approximately 83%. Further studies utilizing short-term (20 min) infusion of BBU prior to administration of FUra suggested that the inhibition of DPD was reversible. While FdUrd phosphorolysis was not affected, subsequent catabolism of FUra decreased by 70%. Studies on isolated hepatocytes indicated that the increased FUra level in perfusate resulted from inhibition of FUra catabolism and not from inhibition of FUra transport. The significant inhibition of FUra catabolism suggests that BBU may be useful in modulating regional chemotherapy by these fluoropyrimidines.
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PMID:Inhibition of fluoropyrimidine catabolism by benzyloxybenzyluracil. Possible relevance to regional chemotherapy. 182 54

Seventeen patients with advanced breast cancer were imaged with a specially collimated gamma camera to study tumor uptake of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) before and during therapy. Fourteen patients (82%) showed increased FDG accumulation in metastatic tumors, 6/8 (75%) of axillary, supra or infraclavicular metastatic lymph nodes were detectable. In one of these cases, FDG imaging was the first method to identify axillary metastasis causing nerve compression. Also, pulmonary and liver metastases could be imaged with FDG; both in two patients. The intra individual variability in uptake was considerable in bone metastases, and some lesions remained FDG negative: 99mTc-DPD was superior in detecting bone disease. Bone metastases of the osteolytic or mixed type were better visualized than sclerotic ones. Ten patients were reimaged later to assess the effect of therapy on FDG uptake. Increased uptake was associated with clinical progression, while unchanged or diminished uptake did not predict the course of disease as reliably. This study indicates that FDG can be used to image breast cancer metastases. FDG may be valuable in monitoring treatment response, but positron emission tomography (PET) would probably be more appropriate than planar imaging for this purpose.
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PMID:[18F]fluorodeoxyglucose scintigraphy in diagnosis and follow up of treatment in advanced breast cancer. 292 Jul 39

We have investigated the clinical efficacy for the detection of bone metastases of two recently marketed bone-seeking radiopharmaceuticals, HDP and DPD, compared with traditionally used MDP. Twenty patients received 15 mCi 99mTc-MDP; after assessment ten of these patients later received 15 mCi 99mTc-DPD and ten other patients of this group were injected with 15 mCi 99mTc-HDP. Scintigraphy took place 3 h after tracer injection. Quantitative analysis included the calculation of normal bone to soft tissue ratios, lesion to soft tissue ratios and lesion to normal bone ratios for all three radiopharmaceuticals. Visual inspection of the scintiphotos revealed the same number of bone lesions at the same localisations. Statistical evaluation of our quantitative data showed that the lesion to normal bone ratio was significantly higher for MDP than for DPD. No further significant differences in the uptake in normal bone or in the metastatic lesions were found between all three radiopharmaceuticals. It is concluded that the new bone-seeking agents DPD and HDP do not possess clinical advantages over MDP for the detection of skeletal metastases.
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PMID:A comparison between the diagnostic efficacy of 99mTc-MDP, 99mTc-DPD and 99mTc-HDP for the detection of bone metastases. 622 Sep 8

The objective of this study was to attempt to identify patient co-variables which could influence interpatient variability in 5-fluorouracil (5-FU) clearance during a 5-day continuous venous infusion (CVI, cisplatin 100 mg/m2 day 1 then 5-FU 1 g/m2/day days 2-6). The analysis was performed using a NONMEM program according to a linear one-compartment model. A total of 186 cycles (2 samples per day, 8 a.m. and 5 p.m.) were analysed from 104 patients with various cancers (the majority of head and neck and oesophagus). The study co-variables were age, sex, body surface area, hepatic metastases, peripheral mononuclear cell dihydropyrimidine dehydrogenase activity (PMNC-DPD), liver enzymes, clock-time (8 a.m. versus 5 p.m.), elapsed time during CVI. The data showed that 5-FU clearance was significantly reduced by increased age, low PMNC-DPD, high serum alkaline phosphatase and elapsed time during infusion. These data may be useful for improving knowledge of predictive factors which can influence 5-FU exposure and thus predispose to toxic manifestations.
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PMID:Co-variables influencing 5-fluorouracil clearance during continuous venous infusion. A NONMEM analysis. 962 44

1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxyuridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihydrofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. 5-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodulation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.
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PMID:5-fluorouracil: a pharmacological paradigm in the use of cytotoxics. 980 59

Biochemical markers of resorption and formation of bone tissue (piridinoline-PD, desoxypiridinoline-DPD and alkaline phosphatase-AP, respectively) were measured in blood serum and urine of 41 prostatic cancer (PC) patients with metastases to the bones and 24 PC patients free of such metastases as well as of 40 healthy males and 11 males with benign prostatic hyperplasia (BPH). It was found that PD, DPD levels, general AP activity and activity of its bone fraction were significantly higher in PC patients with bone metastases than in the others (p < 0.001). The former had a significantly higher percent of peptide-bound and lower percent of free forms of PD and DPD (p < 0.001) vs patients without metastases and controls. Higher biochemical serum and urine indices in PC patients with bone metastases reflect enhanced intensity of both formation and resorption of bone tissue in PC with bone metastatic lesions. Therefore, it is possible to use PD, DPD and AP values in diagnosis and monitoring of metastatic skeletal destruction in PC.
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PMID:[Role of biochemical indices as metastatic markers in patients with prostatic cancer invading skeleton]. 1118 86

UFT and leucovorin (Orzel) is a combination of tegafur and uracil in a molar ratio of 1:4. Tegafur, a prodrug of 5-fluorouracil (5-FU), is converted to 5-FU by the hepatic cytochrome P450 pathway, whereas uracil enhances the half-life of converted 5-FU leading to prolonged exposure and higher intracellular concentration of 5-FU by inhibiting dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in 5-FU catabolism. UFT has broad antitumor activity against colorectal and breast cancer, and has been studied extensively worldwide. Trials conducted in the United States have mainly focused on the combination of UFT and leucovorin. Compared with an intravenous 5-FU plus leucovorin regimen in advanced colorectal cancer treatment, UFT plus leucovorin appears to have equivalent antitumor efficacy with less toxicity. UFT may also provide a more convenient protracted treatment method with fewer complications, compared to intravenous programs. The application for FDA approval of UFT with leucovorin as a first-line treatment regimen for advanced colorectal cancer is pending. Administered as a single agent or in combination with other chemotherapy agents and hormones, UFT may also be effective in treating breast cancer, either as a primary adjuvant treatment or as palliative treatment for metastatic disease.
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PMID:UFT in the treatment of colorectal and breast cancer. 1121 78

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

It is essential for actively proliferating cells to increase their rate of DNA synthesis to progress through the cell cycle. This is reflected in the increased uracil usage that is a common feature in solid tumours. Thymidine phosphorylase (TP) anabolises formation of pyrimidine nucleosides available for DNA synthesis, whereas dihydropyrimidine dehydrogenase (DPD) catabolises the degradation of pyrimidine bases, thereby reducing levels of uracil and thymine available for DNA synthesis. In addition, tissue levels of TP or DPD have been associated with the clinical efficacy of pyrimidine anti-metabolites commonly used in the treatment of colorectal cancer. There is little information, however, on the relative expression or degree of co-ordinated regulation of either protein in primary or metastatic colorectal cancer. DPD and TP protein levels were measured in 15 primary colorectal carcinomas, 10 colorectal liver metastases and 25 adjacent uninvolved tissues. DPD was reduced in 67% (10/15) of colorectal tumours (mean tumour/normal = 0.52) and in all liver metastases (mean tumour/normal = 0.41) compared with the corresponding normal tissue. In contrast, TP was increased in 80% (12/15) of colorectal tumours (mean tumour/normal = 18.91) and in all metastases (mean tumour/normal = 3.70). TP and DPD protein expression were highly variable in uninvolved and tumour tissues. The ratio of TP:DPD was higher in 87% of colorectal tumours and in all liver metastases compared with the adjacent uninvolved tissues. This suggests the presence of co-ordinated regulation of these pyrimidine metabolic enzymes and offers a strategy for optimising the use of pyrimidine-based chemotherapy.
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PMID:Thymidine phosphorylase and dihydropyrimidine dehydrogenase protein expression in colorectal cancer. 1166 12

To evaluate the antitumor efficacy against metastatic breast cancer of fluoropyrimidines alone and combined with other chemotherapeutic agents, we developed a murine model of breast cancer metastatic to the lung by orthotopically implanting MDA-MB-435S breast tumors into mice. MDA tumor cells greatly metastasized to lung tissue only after the orthotopically implanted tumors were surgically removed. Measurement of the expression of enzymes involved in 5-FU metabolism showed significantly higher activity of dihydropyrimidine dehydrogenase (DPD) and lower activity of thymidylate synthase (TS) in the MDA metastases than in the orthotopically implanted tumors. Based on the enzymatic properties of metastatic tumors, the minimum toxic doses of UFT (17.5 mg/kg/day) as a DPD-inhibitory fluoropyrimidine (DIF), and of 5'-DFUR (120 mg/kg/day) as a non-DIF, were orally administered to mice with pulmonary metastasis of the breast tumor. The results showed that UFT significantly inhibited the growth of pulmonary metastases of the breast tumors, but 5'-DFUR did not. UFT seemed to inhibit the growth of the pulmonary metastases of the breast tumors in combination with paclitaxel (50 mg/kg) more than in combination with 5'-DFUR, although the antitumor efficacy of neither combination was significantly different from that of paclitaxel alone. These results suggest that combination of DIF with other chemotherapeutic drugs, such as taxanes, is required to attain high antimetastatic and antitumor efficacy against breast tumor metastases, based on the molecular characteristics of the metastatic tumors.
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PMID:[Antimetastatic and antitumor effects of fluoropyrimidines alone and combined with taxanes in a murine model of breast cancer metastatic to the lung]. 1181 85


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