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)

3',5'-Dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8), one of the lipophilic prodrugs of 5-fluoro-2'-deoxyuridine (FdUrd) was dissolved in an oily lymphographic agent (Lipiodol Ultra-Fluid), which had been studied as a carrier of the anticancer drug for hepatic cancer. The prodrug was administered into the left proper hepatic artery of rabbits bearing VX-2 tumor in the liver in order to examine the anticancer effects and possible adverse effects on nontumorous hepatic cells. Lipiodol or FdUrd-C8*Lipiodol selectively remained in the hepatic cancer area but disappeared from nontumorous parts of the liver 7 days after injection. Tumor growth rates in 1 week of the untreated group, a group given injections of 0.2 ml of Lipiodol alone, and groups given injections of 0.2 ml of Lipiodol containing 30, 50, 70, and 100 mg of FdUrd-C8 were 636, 436, 34.8, 14.9, -2.4, and -10.4% of the size at the time of treatment, respectively. Pathological observation also showed that FdUrd-C8 had a strong anticancer effect on VX-2 tumor growing in the liver of the rabbits. In contrast to the effect on the cancerous cells, that on nontumorous hepatic cells was very slight. In pathological observation, necrosis or degeneration of nontumorous hepatic cells was hardly observed. Plasma glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase levels temporarily rose 1 day after injection but returned to the initial levels within 7 days in all groups.
Cancer Res 1987 Apr 01
PMID:Selective anticancer effects of 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine, a lipophilic prodrug of 5-fluoro-2'-deoxyuridine, dissolved in an oily lymphographic agent on hepatic cancer of rabbits bearing VX-2 tumor. 302 18

The present study characterizes the biochemical, morphological, and histological sites of CCNU-induced hepatotoxicity and investigates the effect of modifiers of drug metabolism on this toxicity. A single oral dose (100 mg/kg) of CCNU caused four- and ninefold increases in serum GOT and GPT respectively 48 h after administration in rats. A 25-fold rise in serum bilirubin, a total loss of bile flow, and a decrease in BSP clearance were also observed. Cytochrome P-450 content and EM-N-demethylase activity were significantly decreased to 88% and 66% of control values respectively. A histopathological time course study of CCNU-induced injury showed a progression of acute inflammation, edema, and fibrin deposition in portal areas over 24 h with necrosis and sloughing of bile duct epithelium at 24 and 36 h. Treatment of rats with PB (40 mg/kg/day for 4 days, i.p.) 24 h prior to CCNU administration protected against CCNU-induced hepatotoxicity. Thus, the levels of serum GOT, GPT, and bilirubin were only 2.5 and 4 times higher than in untreated or PB-treated controls. Histopathological examination also showed reduced severity of bile duct lesions in PB-pretreated animals. In rats receiving both PB and CCNU, bile flow was restored and BSP clearance was increased compared to the CCNU-treated rats. The mixed-function oxidase activity in PB + CCNU-treated rats was not significantly different from that in PB-treated controls. It is concluded that pretreatment of rats with PB can markedly suppress the hepatotoxic manifestations, including histopathological changes, the rise in serum bilirubin, and the cholestasis observed in CCNU-treated rats.
Cancer Chemother Pharmacol 1987
PMID:Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity. II. Biochemical and morphological characterization of the injury and its prevention by phenobarbital. 310 4

Five hundred seventy-six consecutive patients from the surgical, obstetrical, and medical services who had received transfusions of volunteer blood were followed-up at regular intervals for 6 mo. Fifty-three (9.2%) developed acute posttransfusion non A, non B hepatitis. Forty-seven (89%) had an incubation period between 2 and 8 wk. The frequency was not related to the age or sex of the patient, the indications for transfusion, the type of surgery, anesthesia, the presence of perioperative hypotension, or the number of units of blood transfused. There were no cases of fulminant hepatitis. Nineteen of the 53 patients (36%) with acute posttransfusion hepatitis progressed to chronic hepatitis. Development of chronic hepatitis was not related to the age or sex of the patient, the incubation period of the preceding acute hepatitis, the presence of shock or malignancy, or the number of units of blood transfused. Patients with higher levels of alanine aminotransferase during the acute hepatitis were more prone to develop chronic hepatitis. The finding of 9.2% of transfusion-related hepatitis in recipients of hepatitis B surface antigen-screened blood from volunteer donors underscores the potential sequelae of blood transfusion, especially as a source of contribution to the pool of chronic liver disease.
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PMID:Posttransfusion hepatitis in Toronto, Canada. 313 69

Fifty-nine children treated with acute lymphoblastic leukemia (ALL) were evaluated for abnormalities of liver function in order to monitor chemotherapy-induced hepatotoxicity. Twenty-one patients (36%) had elevations of alanine aminotransferase (ALT) in a pattern consistent with either drug-induced hepatocellular injury or non-A, non-B (NANB) hepatitis. These 21 patients (Group 1) were compared with the other 38 children (Group 2) with regard to a number of clinical and laboratory characteristics. Patients in Group 1 were older (P = 0.002) and had lower platelet counts (P less than 0.001) and hemoglobin values (P = 0.075) at diagnosis than Group 2 patients. The median number of units of blood products transfused was significantly greater in Group 1 patients (9.0 versus 1.0 units, P less than 0.001). The two groups were similar with regard to chemotherapy regimens. Children with ALL who present at an older age and who have more marked anemia and thrombocytopenia require more blood transfusions and are more likely to develop elevated ALT values in a pattern consistent with acute or chronic NANB hepatitis. These findings suggest a predominant role of NANB posttransfusion hepatitis--rather than or in addition to chemotherapy-induced hepatic injury--as a cause for elevated ALT values in children with ALL. In view of the potentially serious consequences of NANB hepatitis, a change in transfusion support practices may be warranted.
Cancer 1988 Oct 15
PMID:Elevated serum transaminase values during therapy for acute lymphoblastic leukemia correlate with prior blood transfusions. 313 78

A phase I study of recombinant human tumor necrosis factor (rHu-TNF:PT-050) given by intravenous infusion over 30 min or by intratumoral administration was performed in 53 patients with various types of malignant tumors. The dose of rHu-TNF was started with 0.1 x 10(6) U/body for both intravenous infusion and intratumoral administration and increased to 5 x 10(6) U/body for intravenous infusion and 2 x 10(6) U/body for intratumoral administration. The side effects of rHu-TNF given by intravenous infusion included fever, shaking chills, hypotension, general malaise, nausea, and vomiting, and clinical laboratory tests showed elevations of GOT, GPT, and ALP, etc. Among these, only hypotension was dose-related and was considered to be a dose-limiting factor. The maximum tolerable dose estimated was 1 x 10(6) U/body. The plasma concentration of rHu-TNF after completion of a 30-min infusion was dose-dependent, and the elimination half-life was 0.5-2.4 hr. When the rHu-TNF was administered intratumorally, the frequency of side effects was low compared with intravenous infusion.
Cancer Detect Prev 1988
PMID:Phase I study of recombinant human tumor necrosis factor (rHu-TNF:PT-050). 318 Jan 46

The quianazoline antifolate N10-propargyl-5,8-dideazafolic acid (ICI 155,387), an inhibitor of thymidylate synthetase (TS), was evaluated for clinical toxicity in a phase I trial. The compound was given once every week as a bolus injection. Fourteen patients with advanced cancer were treated at doses of 10-30 mg/m3. Four patients from the lowest to the highest dose developed severe renal toxicity, detected by a reversible decrease in the Cr-EDTA clearance. Hepatotoxicity was observed with transient elevations of alanine aminotransferase (ALT) in 10 patients and alkaline phosphatase in nine patients. Neither the incidence nor the severity of these toxicities was dose related. Two patients developed feelings of fatigue, which in one patient coincided with a decrease in Cr-EDTA clearance. No myelotoxicity, dermatological, gastrointestinal toxicity or mucositis was seen. No tumour responses due to ICI 155,387 occurred. The severity and the erratic nature of the renal side-effects suggest that this schedule cannot be recommended for further development of this compound in Phase II trials.
Eur J Cancer Clin Oncol 1988 Feb
PMID:A phase I evaluation of N10-propargyl-5,8-dideazafolic acid. 335 7

To estimate the number of adults medically eligible to donate blood, the percent of the general population over the age of 16 deferrable by 13 current American Red Cross donor guidelines was calculated using the best available United States data. Categories examined included age, weight, hematocrit, pregnancy, blood pressure, heart disease, diabetes requiring insulin, male homosexual activity since 1977, intravenous drug use, sexual partner of high-risk group member, recent transfusion, history of cancer, and other (medical, surgical, travel history). Sex-specific total eligibility rates were estimated by serial multiplication of individual eligibility rates (1.0 minus deferral rates) to account for the proportionate overlap of independent categories, with corrections for expected associations between categories. The resultant eligibility rates for women (57%) and men (70%) indicate fewer eligible donors than commonly stated. Surrogate testing (ALT, anti-HBc) for non-A, non-B hepatitis would further reduce the percent of eligible donors to 55 and 67%, respectively. Based on the actual numbers of women and men in the population, these calculations indicate that an equal number of women and men are medically eligible to donate.
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PMID:An estimate of blood donor eligibility in the general population. 337 67

Brachytherapy by embolization with radiotherapeutic microspheres following intraarterial infusion of a radiosensitizer represents an attempt to combine several selective modalities into a more potent, focused attack on regionally confined tumors. In pursuit of this goal, we examined the ability of foxhounds with surgically implanted hepatic arterial (HA) delivery systems to tolerate a clinically relevant dosage of HA yttrium-90 (Y-90) by microsphere administration either alone or preceded by a 28-day constant HA infusion of either 5-bromo-2'-deoxyuridine (BUDR) or a control solution. Five dogs received BUDR (10 mg/kg/day) and five a control buffer infusion for 28 days immediately prior to the administration of Y-90-coated 15 micron resin microspheres (equivalent of 5000 rads to the entire liver) to each dog on day 31. In all animals, blood counts, bilirubin, amylase, appetite, weight, and behavior remained unchanged. Dogs receiving the microspheres after buffer infusion alone exhibited no hepatic enzyme alanine aminotransferase or alkaline phosphatase elevation. Alanine aminotransferase and alkaline phosphatase levels both rose during the third week of BUDR infusion, and while subsequent microsphere administration further increased enzyme levels, these levels had largely normalized by necropsy on day 82. At necropsy, the type and degree of hepatic toxicity among the animals receiving radioactive microspheres was comparable to that previously described in patients receiving external beam hepatic irradiation at conventional doses (2000-3000 rads). Also noted was a radiation-induced cholecystitis (due in large part to the gallbladder's total reliance on the hepatic artery for blood supply). One resin microsphere dog exhibited a small quantity of microspheres in the lungs causing focal radiation-induced granulomas suggesting the need to assess shunting of microspheres through the liver in clinical studies. Thus, HA Y-90 microspheres with BUDR can produce acceptable, nonlethal, and tolerable toxicities in this dog model suggesting that clinical studies of this combination are not likely to be contraindicated by synergistic toxicity. Although HA BUDR did not contribute significantly to the toxicity of the Y-90 microspheres, HA BUDR by itself administered uninterrupted for 4 weeks may, like HA FUDR (clinically), cause chemical hepatitis/cholangitis. The unexpected fragmentation of the resin spheres (albeit without myelosuppression) has led us to begin studies with a recently developed nondisruptible glass microsphere (ThereSphere) in which the Y-90 is part of the glass matrix and cannot leach.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1987 Jun 15
PMID:Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs. 358 Oct 69

A four-fold (P less than 0.001) mean increase in iron levels was found in 18 patients (a total of 36 courses of therapy) with ovarian cancer at the end of a 5-day course of cisplatin (40 mg/m2 per day every 4-5 weeks). The kinetics of these modifications began very early (24-48 h after initiation of therapy): they reached their maximum on the 4th-5th day, coinciding with the last drug administration, and basal levels were recovered after the 10th day. A subsequent eight-fold average increase (P less than 0.001) in ferritin serum levels, beginning 2 days after the iron changes, was observed, but showed a slower regression (after the 15th day). Reticulocyte counts were lowered (P less than 0.001) with the same time-course of the iron increases, but returned to pretreatment levels within 2 weeks. Total bilirubin and serum glutamate-pyruvate transaminase showed significantly delayed increases compared with iron. The results are in keeping with a reduced iron utilization by the erythroid precursors, but other mechanisms cannot be excluded. There is no statistical correlation between the early iron increases and the subsequent hemoglobin nadir values.
Cancer Chemother Pharmacol 1987
PMID:Changes in serum iron levels following very high-dose cisplatin. 358 20

The pattern of organ toxicity after single injections of the antitumor agent titanocene dichloride (TDC) in ED90 (40 mg/kg) and LD10 (60 mg/kg) doses to female mice was investigated by analyzing various blood chemical parameters and the composition of urine at intervals between 30 min and 16 days after administration. Whereas the serum levels of electrolytes, blood urea nitrogen, creatinine, total bilirubin and cholesterol did not alter, marked and simultaneous increases in serum concentrations of the enzymes GLDH, GOT and GPT occurred pointing to cellular damage within liver parenchyma; these lesions were apparently reversible within 8 and 16 days after application of TDC even at the LD10 dose. Moreover, glucose concentration decreased immediately after TDC administration, obviously stimulating a regulative output of glucagon and cortisol; these effects were also reversible within 4 to 8 days after TDC administration. No hints to nephrotoxicity induced by TDC became manifest in the present study.
J Cancer Res Clin Oncol 1986
PMID:Pattern of toxicity by titanocene dichloride in mice. Blood and urine chemical parameters. 373 55


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