Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One hundred and eighty seven patients (155 males, 32 females) with histologically proven and previously untreated head and neck cancer were entered in the study. A total of 222 cycles of therapy were analyzed (cisplatin 100 mg m-2 on day 1 and 5-day continuous intravenous infusion of 5-FU 550-1069 mg m-2 day-1, mean 875.5 mg m-2 day-1). Significant interpatient variability for various 5-FU pharmacokinetic parameters was observed including an almost ten-fold range in 5-FU clearance (5-FU Cl, ml min-1 m-2 = 791-7769, mean 2820.7). Log 5-FU Cl was not modified by 5-FU dose (r = -0.1034, P = 0.124, n = 222). Poor linear correlations between log 5-FU Cl and hepatic function tests were observed (respective r and P values for 222 cycles, log AST:0.0526, 0.4365; Log ALT: -0.1167, 0.0842; Log A1K. Phos.:0.154, 0.0214; Log GGT: 0.0652, 0.3436; Log LDH: -0.0984, 0.1563; Log bilirubin: 0.1278, 0.0601). The log 5-FU Cl was also poorly correlated with the serum concentration of various nutritional proteins (respective r and P values for 222 cycles, Albumin: 0.0110, 0.8714; prealbumin: -0.1067, 0.1129; transferrin: 0.0439, 0.5226). Laboratory data including indices of hepatic function and nutritional status cannot account for the interpatient variability in 5-FU disposition.
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PMID:No effect of dose, hepatic function, or nutritional status on 5-FU clearance following continuous (5-day), 5-FU infusion. 849 17

According to the data obtained from the fundamental investigations using flow cytometry we designed the schedule of combination chemotherapy for solid cancer patients and we tried this therapy on 25 patients with non-curative, unresectable and recurrent cancers: 9 gastric, 5 colo-rectal, 3 esophageal, 3 pancreatic, 2 gall bladder, 2 lung and 1 breast cancer. The treatment was performed every 3 or 4 weeks as follows: CDDP 70 mg/m2 (d.i.), PEP 4 mg/m2 (i.v.) and MMC 4 mg/m2 (i.v.) on day 1, ADM 15 mg/m2 (i.v.) on day 4, and 5-Fu 250 mg/body (d.i.) every day. Among 22 patients evaluated completely, 1 complete response, 9 partial responses, 11 no changes, 1 progressive disease were obtained. The overall response rate was 45%. From the comparison of survival curves, survival rate was significantly better in patients responded to this therapy than in patients who did not respond to it (p less than 0.05). As for side effects, myelosuppression occurred in 19 patients (86%), increase of BUN and/or creatinine were observed in 3 patients (14%), increase of GOT and/or GPT were seen in 10 patients (45%), gastrointestinal symptoms and alopecia were observed in almost all patients, but all of these toxicity were transient and did not impede the continuous treatment.
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PMID:[Chemotherapy for advanced and recurrent cancer patients--the effect of combination chemotherapy using cisplatin, peplomycin, mitomycin C, adriamycin, and 5-fluorouracil]. 170 39

As adverse reactions to the combination treatment by the digestive system, we observed the occurrence of nausea and vomiting in 15% of the cases who received FTP treatment consisting of 5-FU, toyomicin and prednisone, 25% of the cases who received MFU treatment consisting of MMC, 5-FU and ACNU, and in 64% of the cases who received PPQ treatment consisting of CDDP, Carboquone (CQ) and prednisone. The antiemetics usually used are metoclopramide and droperidol, and we preadminister valproate preparation when persistent and delayed emesis is predicted. Several randomized trials have been made, and good efficacies with drugs such as metoclopramide, domperidone and steroid have been reported. Efficacy was good with acute emesis, but nonexistent with delayed emesis. As to the liver injury, in our combination treatment, only one case showed elevation of GPT by more than 500 units in the cases treated with MFU, while, increase in liver enzymes in the blood was observed in 10-20% of the cases. Similarly, there were not so many cases of liver injury during PPQ treatment. Thus, liver injury due to carcinostatic would be less frequent. Moreover, autopsy revealed hepatocellular-type of liver injury, cholestatic type liver injury and fatty metamorphosis at reasonable incidence. There were no typical cases of veno-occlusive disease which are noticed recently. The most important point for prevention and countermeasures against liver injury is to be careful not to use the previously mentioned drugs exhibiting toxicity in the liver if hepatic disease exists.
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PMID:[Adverse reactions to carcinostatics and countermeasures]. 249 62

Postoperative intraportal anti-cancer chemotherapy was used for 51 patients with curatively resected colorectal cancer who were selected in the randomized controlled study to evaluate its inhibitory effect on liver metastasis from colo-rectal cancer. In cases of intraportal chemotherapy, 30 mg of Mitomycin-C (in 3 doses) and 5 mg/kg (B.W.)/day (1985-1986) or 3 mg/kg/day (1987-1988) of 5-FU was injected through the catheter inserted into the portal vein during postoperative 14 days. In cases of the control group (58 patients), the same doses of the drugs were injected into the peripheral vein during the same term. Six patients with recurrences were observed in the intraportal chemotherapy group, and 3 of them had liver metastases. In the control group, more liver metastases were observed (5 of 7 recurrences were liver metastases). Intraportally injected 5 mg/kg/day of 5-FU slightly disturbed the liver function. The averages of the serum GOT, GPT and gamma-GTP level of these cases were higher than those of the control cases. Three mg/kg/day of intraportally injected 5-FU had no influence on the liver function. There were no differences in the incidence of leukocytopenia or thrombocytopenia between the two groups.
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PMID:[Effects of prophylactic intraportal chemotherapy on liver function, blood profile and survival in patients with colo-rectal cancer]. 250 34

For the investigation of locoregional chemotherapy of liver neoplasms we developed a standardized animal model in the rat. Continuous infusion therapy or repeated bolus injections of FUDR or 5-FU were given via the hepatic artery, the portal vein or the vena cava in tumor-bearing animals. The efficacy of the treatment was determined by measuring the tumor volume 3 weeks after tumor cell implantation. For the evaluation of the local and systemic toxicity serum GOT, GPT, and total bilirubin were determined. DNA single strand breaks were assessed in isolated liver and bone marrow cells. Inhibition of colony formation of bone marrow stem cells was determined by CFU-C and CFU-S bioassay. A significant reduction of tumor growth was observed only after continuous infusion of FUDR via the hepatic artery. Systemic toxicity was lowest in this group for both compounds while the local liver toxicity was only slightly elevated.
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PMID:Experiments on the efficacy and toxicity of locoregional chemotherapy of liver tumors with 5-fluoro-2'-deoxyuridine (FUDR) and 5-fluorouracil (5-FU) in an animal model. 293 47

A phase I study of a new floxuridine derivative, FF-705, was performed in patients with various types of solid tumors. Efficacy of single oral administration with dose range of 300 to 700 mg/body was studied in 12 patients. At a dose of 500 mg/body transient increases of s GOT and s GPT were noted in one patient and, of 700 mg/body, nausea, vomiting or stomach dullness sensation was noted in two patients. The maximum tolerated dose was considered to be 700 mg/body or more. The dose limiting factor was a gastrointestinal toxicity. Oral administration in five consecutive days was studied in 23 patients to doses ranging 100 to 700 mg/body. The incidence of side effects were increased with dose escalation, and at a dose of 700 mg/body side effects were seen in all patients. The maximum tolerated dose was considered to be 700 mg/body/day, and the dose limiting factor was gastrointestinal toxicity. The optimal dose of FF-705 for consecutive administration is considered to be within the range of 200 to 300mg/body/day. Serum and urine concentrations of metabolites were assayed in 7 patients receiving single dose of 600 mg/body. In all patients serum concentration of floxuridine (FUDR) was higher than that of 5-FU and other metabolites at all points of measurement. The highest concentration of FUDR was detected at 2 hours after drug administration and the mean value was 0.04 microgram/ml. The main metabolite in the urine was 5'-acetyl-FUDR which was excreted 0.8% to the dose for 24 hours. The other metabolites were excreted less than 0.2%.
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PMID:[Phase I study of a new floxuridine derivative, 2'-deoxy-3', 5'-di-O-acetyl-5-fluoro-3-(3-methylbenzoyl)uridine (FF-705)]. 623 54

It has been reported that 5'-DFUR is converted to 5-FU by uridine phosphorylase in experimental animal tumors. The conversion of thymidine, uridine and 5'-DFUR as substrates was studied in tumor and normal tissues of human and animals. A further series of studies was performed using 1-(2'-deoxy-beta-D-glucopyranosyl) thymine (GPT), a specific inhibitor of uridine phosphorylase. We found that this conversion in human tumors was catalyzed not by uridine phosphorylase but by thymidine phosphorylase. It was also confirmed that the enzyme activities in various human cancers were significantly several times higher than those in adjacent normal tissues. We succeeded in tried and isolating thymidine phosphorylase in a fairly pure form, from which enzyme Km values were calculated. After administration of 5'-DFUR intravenously or orally to patents, tissue and blood samples were collected by biopsy or surgical operation to determine the 5-FU level. The 5-FU levels were always higher in tumor tissues than in the blood or in normal tissues. Finally effective clinical efficacy was demonstrated by oral administration of 5'-DFUR.
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PMID:[5'-Deoxy-5-fluorouridine enzymatic activation from the masked compound to 5-fluorouracil in human malignant tissues]. 623 13

TT-62 is a new derivative of FdUMP, which is the active metabolite of 5-FU. A phase I clinical study of TT-62 was conducted by a cooperative study. The same patients received single and 2-week oral administration of TT-62. Starting from 60 mg/m2 (1n), the dose was escalated to 420 mg/m2 (7n). In the single administration, the maximum tolerated dose (MTD) could not be determined. In the 2-week administration, MTD was 420 mg/m2, and the dose limiting factor was gastro-intestinal disturbances such as anorexia, nausea, vomiting and diarrhea. Increases in GOT.GPT and a decrease in hemoglobin content were observed. After administration was stopped all side effects disappeared. TT-62 was detected mainly in the plasma, while trace amounts of 5-FU and FUdR were also detected. TT-62 was excreted mostly in the urine, as alpha-fluoro-beta-alanine (FBAL). The cumulative urinary excretion of FBAL was about 80% of the total dose, and the oral absorption of TT-62 was thus thought to be good.
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PMID:[Phase I clinical study of TT-62. Research group of TT-62]. 843 62

The effect of anti-cancer drugs on the metabolic efficiency of the liver was evaluated by means of phenazone (antipyrine) kinetics individually in each rat. Chlormethine (nitrogranulogen, NG), methotrexate (MTX), floxuridine (fluorouracil, 5-fluorouracil, 5-FU), cyclophosphamide (CY, endoxan), and three cytostatics applied jointly (MTX + 5-FU + CY) were administered ip to the rats, while antipyrine was given intravenously. The anti-cancer drugs: NG, MTX, 5-FU, CY and MTX + 5-FU + CY delayed the elimination of antipyrine. Statistically significant prolongation of the half-life, decrease in the elimination rate constant and the clearance of antipyrine have been found in the rats receiving anti-cancer drugs, as compared to the controls. After the administration of MTX, 5-FU, CY and the joint administration of MTX + 5-FU + CY the volume of distribution did not change, while the volume of distribution of antipyrine decreased after the administration of NG. The activity of the investigated enzymes, i.e., alanine aminotransferase (ALAT), aspartic aminotransferase (AspAT), gamma-glutamyltransferase (GGT), alkaline phosphatase (AP), which are the indicators of various liver dysfunctions, did not change after the administration of NG, MTX, 5-FU, CY and MTX + 5-FU + CY. The administered antineoplastic drugs in mono and polytherapy changed the activity of oxidase mixed function responsible for the metabolism of antipyrine. CY administered to rats in polytherapy had less influence on liver metabolic efficiency than in monotherapy.
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PMID:Effect of some anti-cancer drugs and combined chemotherapy on the pharmacokinetics of antipyrine in the rat. 886 74

To elucidate the combined effects of fadrozole (nonsteroidal aromatase inhibitor) and tamoxifen, 11 postmenopausal patients with recurrent breast cancer were examined between October 1996 and June 1998. One patient, 49 years old, was ineligible due to the short period after castration. The patients were aged 53-71 years (mean 63.5). PS was 0-1. Six patients were pre-treated with tamoxifen and 6 with oral 5-FU derivatives. One had no previous treatment. The target lesions were soft tissues in 5, bone in 4, lungs in 6 and liver in 1. The response was CR in 2, PR in 2, SD (longer than 24 weeks) in 2, NC in 1 and PD in 3. Consequently, the response rate was 60% (6 out of 10 eligible cases). Hormonal concentration was measured before and after administration of two drugs in weeks 2, 4, 6, 8 and at the end of the treatment, and significant decreases in estrogens in peripheral blood were observed. Adverse effects (4 cases of low grade headache, dizziness and elevation of GOT, GPT, gamma-GTP) did not influence the continuous administration of the drugs. We conclude that combined administration of fadrozole (2nd generation aromatase inhibitor) and tamoxifen produces a good response in postmenopausal recurrent breast cancer patients, and can be a useful treatment for patients with breast cancer.
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PMID:[A combined effect of fadrozole and tamoxifen in postmenopausal patients with recurrent breast cancer: a preliminary report: Japanese Cooperative Study Group of Fadrozole and Tamoxifen]. 1105 22


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