allopurinol and Liver-Neoplasms

Primary liver tumours and liver metastases from colorectal carcinoma are two of the most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the people with metastatic liver disease will die from metastatic complications. Electrocoagulation by diathermy is a method used to destroy tumour tissue, using a high-frequency electric current generating high temperatures, applied locally with an electrode (needle, blade, or ball). The objective of this method is to destroy the tumour completely, if possible, in a single session. With the time, electrocoagulation by diathermy has been replaced by other techniques, but the evidence is unclear.. To assess the beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus no intervention, other ablation methods, or systemic treatments in people with liver metastases.. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, CINAHL, ClinicalTrials.gov, ICTRP, and FDA to October 2020.. We considered all randomised trials that assessed beneficial and harmful effects of electrocoagulation by diathermy, administered alone or with another intervention, versus comparators, in people with liver metastases, regardless of the location of the primary tumour.. We used standard methodological procedures expected by Cochrane. We assessed risk of bias of the included trial using predefined risk of bias domains, and presented the review results incorporating the certainty of the evidence using GRADE.. We included one randomised clinical trial with 306 participants (175 males; 131 females) who had undergone resection of the sigmoid colon, and who had five or more visible and palpable hepatic metastases. The diagnosis was confirmed by histological assessment (biopsy) and by carcinoembryonic antigen (CEA) level. The trial was conducted in Iraq. The age of participants ranged between 38 and 79 years. The participants were randomised to four different study groups. The liver metastases were biopsied and treated (only once) in three of the groups: 75 received electrocoagulation by diathermy alone, 76 received electrocoagulation plus allopurinol, 78 received electrocoagulation plus dimethyl sulphoxide. In the fourth intervention group, 77 participants functioning as controls received a vehicle solution of allopurinol 5 mL 4 x a day by mouth; the metastases were left untouched. The status of the liver and lungs was followed by ultrasound investigations, without the use of a contrast agent. Participants were followed for five years. The analyses are based on per-protocol data only analysing 223 participants. We judged the trial to be at high risk of bias. After excluding 'nonevaluable patients', the groups seemed comparable for baseline characteristics. Mortality due to disease spread at five-year follow-up was 98% in the electrocoagulation group (57/58 evaluable people); 87% in the electrocoagulation plus allopurinol group (46/53 evaluable people); 86% in the electrocoagulation plus dimethyl sulphoxide group (49/57 evaluable people); and 100% in the control group (55/55 evaluable people). We observed no difference in mortality between the electrocoagulation alone group versus the control group (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.94 to 1.03; 113 participants; very low-certainty evidence). We observed lower mortality in the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus the control group (RR 0.87, 95% CI 0.80 to 0.95; 165 participants; low-certainty evidence). We are very uncertain regarding post-operative deaths between the electrocoagulation alone group versus the control group (RR 1.03, 95% CI 0.07 to 16.12; 152 participants; very low-certainty evidence) and between the electrocoagulation combined with allopurinol or dimethyl sulphoxide groups versus the control group (RR 1.00, 95% CI 0.09 to 10.86; 231 participants; very low-certainty evidence). The trial authors did not report data on number of participant. The evidence on the beneficial and harmful effects of electrocoagulation alone or in combination with allopurinol or dimethyl sulphoxide in people with liver metastases is insufficient, as it is based on one randomised clinical trial at low to very low certainty. It is very uncertain if there is a difference in all-cause mortality and post-operative mortality between electrocoagulation alone versus control. It is also uncertain if electrocoagulation in combination with allopurinol or dimethyl sulphoxide may result in a slight reduction of all-cause mortality in comparison with a vehicle solution of allopurinol (control). It is very uncertain if there is a difference in post-operative mortality between the electrocoagulation combined with allopurinol or dimethyl sulphoxide group versus control. Data on other adverse events and complications, failure to clear liver metastases or recurrence of liver metastases, time to progression of liver metastases, tumour response measures, and health-related quality of life were most lacking or insufficiently reported for analysis. Electrocoagulation by diathermy is no longer used in the described way, and this may explain the lack of further trials.

Topics: Adult; Aged; Allopurinol; Cause of Death; Colonic Neoplasms; Dimethyl Sulfoxide; Electrocoagulation; Female; Humans; Liver Neoplasms; Male; Middle Aged; Randomized Controlled Trials as Topic; Solvents

Topics: Adult; Aged; Allopurinol; Autoantibodies; Carcinoma, Hepatocellular; Diagnosis, Differential; Disease Progression; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin A; Immunosuppressive Agents; Incidence; Liver; Liver Neoplasms; Male; Middle Aged; Prognosis; Risk Factors; Survival Rate

Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Electro-coagulation is the coagulation (clotting) of tissue using a high-frequency electrical current applied locally with a metal instrument or needle with the aim of stopping bleeding. The object of this technique is to destroy the tumour completely, if possible, in a single surgical session.. To study the beneficial and harmful effects of electro-coagulation compared with no intervention, to other ablation methods, or systemic treatments in patients with liver metastases.. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012.. We included one randomised clinical trial that assessed beneficial and harmful effects of electro-coagulation and its comparators in patients with liver metastases, irrespective of the location of the primary tumour.. We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures as well as information on the design and methodology of the trials. Risk of bias of the trials and data extraction was carried out by one author and checked by a second author.. We included one randomised clinical trial that compared four groups: electro-coagulation alone, electro-coagulation + dimethyl sulphoxide, electro-coagulation + allopurinol, and control (Salim 1993). The risk of bias in the trial is high. In three groups, patients had their metastases destroyed with diathermy electro-coagulation (current set at No 5) and received: 1) solution of allopurinol by mouth 5 mL 4 x a day or 2) allopurinol by mouth 5 mL (50 mg) 4 x a day or 3) dimethyl sulphoxide by mouth 5 mL (500 mg) 4 x a day. In the control group patients received a solution of allopurinol by mouth 5 mL 4 x a day. The treatment was started in the fifth postoperative day and was continued for five years. Three hundred and six patients who had undergone resection of the sigmoid colon and who had five or more hepatic metastases were included; 75 received electro-coagulation alone (58 were evaluable), 76 received electro-coagulation plus allopurinol (53 were evaluable), 78 received electro-coagulation plus dimethyl sulphoxide (57 were evaluable), and 77 were in the control group (55 evaluable).The authors reported the number of deaths due to disease spread (100% in the control, 98% in electro-coagulation, 87% in electro-coagulation + allopurinol, and 86% in the electro-coagulation + dimethyl sulphoxide groups). There was a significant benefit in favour of the electro-coagulation + allopurinol (risk ratio (RR) 0.87 (95% confidence interval (CI) 0.78 to 0.96)) and electro-coagulation + dimethyl sulphoxide (RR 0.86 (95% CI 0.77 to 0.95)) groups compared to the control group, but no such benefit in the electro-coagulation alone group (RR 0.98 (95% CI 0.95 to 1.02)) compared to the control group. There were no local recurrences, no positive tests for occult blood, and observed pulmonary metastases were always with ultrasonographic evidence of hepatic secondaries and were not significantly different for the experimental groups compared to the control group (electro-coagulation: RR 1.11 (95% CI 0.4 to 3.09)), electro-coagulation + allopurinol (RR 0.86 (95% CI 0.28 to 2.66)), electro-coagulation + dimethyl sulphoxide (RR 0.8 (95% CI 0.26 to 2.48)). None of the adverse events were significantly associated with treatment.. On the basis of one randomised trial which did not describe its methodology in sufficient detail to assess risk of bias and quality, excluded 27% of patients after randomisation due to various reasons, and is probably not free from selective outcome reporting bias, there is insufficient evidence to conclude that in patients with colonic cancer liver metastases, electro-coagulation alone brings any significant benefit in terms of survival or recurrence compared with the control. In addition, there is insufficient evidence for the effectiveness of adding allopurinol or dimethyl sulphoxide to electro-coagulation. The probability for selective outcome reporting bias in the trial is high. More randomised trials are needed in order to sufficiently validate electro-coagulation with or without co-interventions.

Topics: Allopurinol; Colonic Neoplasms; Dimethyl Sulfoxide; Electrocoagulation; Humans; Liver Neoplasms; Randomized Controlled Trials as Topic; Solvents

To explore the protective effect of propofol on liver during hepatic ischemia/reperfusion injury (HIRI) and its mechanisms in patients undergoing liver surgery.. Eighteen patients who were scheduled for selective hepatic surgery were randomly divided into control group (n=9) and propofol treatment group (n=9). Changes of several parameters in plasma and effects of propofol on them were observed before liver ischemia, at end of ischemia and at reperfusion for 25 minutes, parameters of which included superoxide dismutase (SOD), xanthine oxidase (XO), lipid peroxide (LPO) and alanine aminotransferase (ALT) activity, and the ultrastructure changes in liver tissue were observed under electron microscope at 25 minutes after reperfusion.. SOD activity decreased remarkably (P<0.01); XO activity, LPO concentration and ALT value increased significantly (P<0.01) during HIRI, and there were abnormal changes of the hepatic ultrastructure at 25 minutes after reperfusion. Afer treatment with propofol, the variation of all parameters were alleviated markedly (P<0.05 and P<0.01).. Propofol has protective effects on HIRI by reducing oxygen free radical level and inhibiting lipid peroxidation after hepatic ischemia/reperfusion in patients undergoing liver cancer surgery.

Topics: Adult; Carboxypeptidases; Female; Free Radical Scavengers; Humans; Lipid Peroxides; Liver; Liver Neoplasms; Male; Middle Aged; Propofol; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Xanthine Oxidase

Regional therapy for colorectal liver metastases aimed at prolonging survival has not been tested fully in a randomized trial with untreated control subjects. This study explored the efficacy of temporary hepatic artery occlusion followed by intraportal infusion of 5-fluorouracil (5-FU) and oral allopurinol as biochemical modulators in prolonging the survival of patients with nonresectable liver metastases and no extrahepatic cancer.. Eighty-four patients were considered for randomization, of whom 24 were excluded at laparotomy because of extrahepatic cancer (n = 17) or resectable lesions (n = 5). In two patients, no cancer was identified in the liver. Thirty-two patients were allocated to receive treatment, and 28 were allocated to receive no regional or systemic treatment. Six patients were excluded after randomization because of major protocol violations.. The median survival time for patients was 17 months (range, 0-66), and for control subjects, the median was 8 months (range, 0-31). Log rank analysis demonstrated a significant survival benefit for treatment versus no treatment (P = 0.0039). (In two patients, early death was due to toxicity from the wrong dose of 5-FU and the wrong route of administration, respectively; the mean and median survival were reduced by 1 month).. This study identified a treatment modality that prolongs survival in patients with nonresectable liver metastases and no extrahepatic metastases from colorectal cancer, suggesting that control subjects receiving no therapy may not be necessary in future randomized trials.

Topics: Administration, Oral; Adult; Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Constriction; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intravenous; Liver Neoplasms; Male; Middle Aged; Portal Vein; Survival Analysis; Treatment Outcome

The influence of oxygen-derived free radicals on survival in advanced colonic cancer was assessed in a prospective randomized controlled double-blind trial using the radical scavengers dimethyl sulphoxide (DMSO) and allopurinol. Following palliative sigmoid colectomy for carcinoma at Dukes' stage D, 306 patients were randomized to the control group or to electrocoagulation of liver secondaries alone or with allopurinol (50 mg by mouth 4 times a day) or DMSO (500 mg by mouth 4 times a day). In 193 fully evaluable patients who were studied for 5 years, allopurinol and DMSO incurred a significant (p < 0.05) survival advantage over the whole period of study. The similarity in efficacy between allopurinol and DMSO and the fact that the only action they share is scavenging oxyradicals, suggest that these radicals mediate the detrimental effects of malignancy and that removing them incurs a survival advantage for patients with advanced colonic cancer.

Topics: Adenocarcinoma; Adult; Aged; Allopurinol; Analysis of Variance; Colonic Neoplasms; Dimethyl Sulfoxide; Double-Blind Method; Electrocoagulation; Female; Free Radical Scavengers; Humans; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Reactive Oxygen Species; Sigmoid Neoplasms; Survival Rate

Tumour lysis syndrome (TLS) is a rare oncological emergency in solid tumours. Because it is associated with bad short-term prognosis, early recognition and treatment are mandatory. This case refers to a middle-aged woman who presented with stage IV colon cancer, with massive hepatic involvement. After three cycles of first-line FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin), she developed acute kidney injury and hyperkalaemia that did not respond to standard measures. High suspicion of TLS prompted further corroborating investigations and early intensive care unit admission. With vigorous hydration and allopurinol, TLS completely resolved and the patient was discharged. Prophylaxis of subsequent TLS recurrence was complicated by biopsy-proven neutrophilic vasculitis secondary to allopurinol. Prevention of TLS with hydration and rasburicase was performed prior to each subsequent cycle of chemotherapy. This case report is intended to highlight risk factors for TLS in solid tumours and focus on treatment and secondary prophylaxis of TLS.

Topics: Adenocarcinoma; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diagnosis, Differential; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Palliative Care; Tomography, X-Ray Computed; Tumor Lysis Syndrome

Combination treatment with low-dose thiopurine and allopurinol (AP) has successfully been used in patients with inflammatory bowel disease with a so called skewed thiopurine metabolite profile. In red blood cells in vivo, it reduces the concentration of methylated metabolites and increases the concentration of the phosphorylated ones, which is associated with improved therapeutic efficacy. This study aimed to investigate the largely unknown mechanism of AP on thiopurine metabolism in cells with an active thiopurine metabolic pathway using HepG2 and HEK293 cells. Cells were treated with 6-mercaptopurine (6MP) and AP or its metabolite oxypurinol. The expression of genes known to be associated with thiopurine metabolism, and the concentration of thiopurine metabolites were analyzed. Gene expression levels were only affected by AP in the presence of 6MP. The addition of AP to 6MP affected the expression of in total 19 genes in the two cell lines. In both cell lines the expression of the transporter SLC29A2 was reduced by the combined treatment. Six regulated genes in HepG2 cells and 8 regulated genes in HEK293 cells were connected to networks with 18 and 35 genes, respectively, present at known susceptibility loci for inflammatory bowel disease, when analyzed using a protein-protein interaction database. The genes identified as regulated as well as the disease associated interacting genes represent new candidates for further investigation in the context of combination therapy with thiopurines and AP. However, no differences in absolute metabolite concentrations were observed between 6MP+AP or 6MP+oxypurinol vs. 6MP alone in either of the two cell lines. In conclusion; the effect of AP on gene expression levels requires the presence of 6MP, at least in vitro. Previously described AP-effects on metabolite concentrations observed in red blood cells in vivo could not be reproduced in our cell lines in vitro. AP's effects in relation to thiopurine metabolism are complex. The network-identified susceptibility genes represented biological processes mainly associated with purine nucleotide biosynthetic processes, lymphocyte proliferation, NF-KB activation, JAK-STAT signaling, and apoptotic signaling at oxidative stress.

Topics: Allopurinol; Antimetabolites; Carcinoma, Hepatocellular; Drug Therapy, Combination; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; HEK293 Cells; Humans; Liver Neoplasms; Mercaptopurine; Methyltransferases; Purines

A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC50 values of 25.5 and 35.2 μM against human hepatoma carcinoma cell lines, BEL-7402 and SMMC-7221, respectively. The anticancer activity of 4 was comparable to that of Tanespimycin (17-N-allylamino-17-demethoxy geldanamycin, 17-AAG) that inhibited the growth of BEL-7402 and SMMC-7221 cells at IC50 values of 12.4 and 9.85 μM, respectively. However, unlike allopurinol, which is also a strong inhibitor of XOD, compound 4 is a much weaker XOD inhibitor, suggesting that the anticancer activities of the allopurinol derivatives may not be associated with XOD inhibition. Moreover, the cytotoxicity of 4 toward normal cells is significantly lower than that of 17-AAG, making 4 a promising lead compound for further optimization of structure-activity relationships that may lead to anticancer agents of clinical utility.

Topics: Allopurinol; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Liver Neoplasms; Molecular Structure; Structure-Activity Relationship; Xanthine Oxidase

Cachexia is a common complication of cancer and may be responsible for 22% of all cancer-related deaths. The exact cause of death in cancer cachexia patients is unknown. Recently, atrophy of the heart has been described in cancer cachexia animal models, which resulted in impaired cardiac function and is likely to contribute to mortality. In cancer patients hyperuricaemia independent of tumour lysis syndrome is often associated with a worse prognosis. Xanthine oxidase (XO) metabolizes purines to uric acid and its inhibition has been shown to improve clinical outcome in patients with chronic heart failure.. The rat Yoshida AH-130 hepatoma cancer cachexia model was used in this study. Rats were treated with 4 or 40 mg/kg/d oxypurinol or placebo starting one day after tumour-inoculation for maximal 15 days. Cardiac function was analyzed by echocardiography on day 11.. Here we show that inhibition of XO by oxypurinol significantly reduces wasting of the heart and preserves cardiac function. LVEF was higher in tumour-bearing rats treated with 4 mg/kg/d (61±4%) or 40 mg/kg/d (64±5%) oxypurinol vs placebo (51±3%, both p<0.05). Fractional shortening was improved by 4 mg/kg/d (43±3%) oxypurinol vs placebo (30±2, p<0.05), while 40 mg/kg/d oxypurinol (41±5%) did not reach statistical significance. Cardiac output was increased in the 4 mg/kg/d dose only (71±11 mL/min vs placebo 38±4 mL/min, p<0.01).. Inhibition of XO with oxypurinol has beneficial effects on cardiac mass and function in a rat model of severe cancer cachexia, suggesting that XO might be a viable drug target in cancer cachexia.

Topics: Animals; Cachexia; Cardiomyopathies; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Oxypurinol; Rats; Rats, Wistar; Xanthine Oxidase

Topics: Adenocarcinoma; Administration, Topical; Allopurinol; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Colonic Neoplasms; Drug Eruptions; Free Radical Scavengers; Humans; Injections, Intravenous; Liver Neoplasms; Male; Middle Aged; Ointments; Treatment Outcome

Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity.. Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively.. Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil.. The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Antimetabolites, Antineoplastic; Carcinoma, Pancreatic Ductal; Cell Death; Cell Line, Tumor; Cytotoxicity, Immunologic; Deoxycytidine; DNA Damage; Female; Gallbladder Neoplasms; Gemcitabine; Gene Expression; Histocompatibility Antigens Class I; Humans; Kaplan-Meier Estimate; Killer Cells, Natural; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Peritoneal Neoplasms; Uric Acid; Xanthine Dehydrogenase

Primary human hepatocytes are clinically used for transplantation or in bioartificial liver devices for the treatment of patients with liver failure. We aimed to assess whether an organ preservation solution containing trehalose, namely ET-Kyoto solution (ETK), could improve human liver cell viability when used for cryopreservation in comparison to the University of Wisconsin solution (UW). Our study showed beneficial effects of ETK when used in combination with other cryoprotectants on the viability of thawed hepatocytes. Indeed, no significant difference was seen between the viability of freshly isolated cells and cryopreserved cells when cryopreserved with ETK combined with other cryoprotectants. In contrast, a significant decrease of viability was observed in cells cryopreserved with UW or ETK combined with dimethysulfoxide (DMSO) only, or with UW combined with other cryoprotectants, compared to freshly isolated cells. No significant difference was observed between the four different groups of cryopreserved hepatocytes with regards to cell recovery rate or cell attachment after thawing. However, a significant decrease in cell metabolic activity was found in cells cryopreserved with UW 10% DMSO compared to the other groups. In conclusion, our study confirms the beneficial effect of ETK for the cryopreservation of human hepatocytes in combination with other cryoprotective agents.

Topics: Adenosine; Adult; Aged; Allopurinol; Cell Culture Techniques; Cell Survival; Female; Gluconates; Glutathione; Hepatectomy; Hepatocytes; Humans; Hydroxyethyl Starch Derivatives; Insulin; Liver Neoplasms; Male; Middle Aged; Organ Preservation Solutions; Phosphates; Raffinose; Tissue Preservation; Trehalose

A 77-year-old-man was admitted to hospital for treatment of a huge hepatocellular carcinoma by transarterial chemoembolization. After treatment, the patient developed acute tumor lysis syndrome with hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis and acute renal failure, which was successfully treated. In the treatments of solid organ tumors, acute tumor lysis syndrome is an extremely rare complication. To the best of the authors' knowledge, this patient is the third case of such a complication after transarterial chemoembolization for a hepatocellular carcinoma in the English literature.

Topics: Aged; Allopurinol; Antimetabolites; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Length of Stay; Liver Neoplasms; Male; Radiography; Rehydration Solutions; Sodium Bicarbonate; Treatment Outcome; Tumor Lysis Syndrome

University of Wisconsin (UW) and histidine-tryptophan-ketoglutarate (HTK) solutions are the 2 most commonly used liver preservation solutions. The aim of this study was to compare cardiovascular stability, acid-base status, and potassium concentrations between patients who received grafts preserved in either UW or HTK solution in orthotopic liver transplantation (OLT).. In this retrospective study, 87 patients who underwent living donor OLT were divided into 2 groups: UW (n = 28) and HTK (n = 59). Group HTK was subdivided into group NF-HTK (n = 31; nonflushed before reperfusion) and group F-HTK (n = 28; flushed before reperfusion). We determined mean arterial pressure (MAP) and heart rate every minute for 5 minutes after reperfusion and the maximum change in these values and incidence of postreperfusion syndrome (PRS). Body temperature, cardiovascular and acid-base parameters, as well as potassium concentrations were compared at 5 minutes before and 5 and 30 minutes after reperfusion.. The maximum decreases in MAP within 5 minutes after reperfusion were significantly greater in both the NF-HTK and the F-HTK groups. The rate of PRS was significantly greater in the NF-HTK compared with the UW group. Flushing with HTK solution decreased the rate of PRS; there was no significant difference between the F-HTK and UW groups. All serial changes in body temperature, cardiovascular and acid-base parameters, as well as potassium concentrations were similar among the 3 groups.. The incidence of PRS was greater using HTK compared with UW solution during the reperfusion period. Therefore, careful hemodynamic management is advised when using HTK solution.

Topics: Acid-Base Equilibrium; Adenosine; Adult; Allopurinol; Blood Pressure; Carcinoma, Hepatocellular; Female; Glucose; Glutathione; Hemodynamics; Humans; Insulin; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Mannitol; Middle Aged; Organ Preservation Solutions; Portal Vein; Potassium; Potassium Chloride; Procaine; Raffinose; Reperfusion Injury; Retrospective Studies

Oxidative stress mediates cell injury during ischaemia/reperfusion. On the other hand, experimental findings suggest that ROS (reactive oxygen species) induce processes leading to ischaemic preconditioning. The extent and source of oxidative stress and its effect on antioxidant status in the human liver during intermittent ischaemia and reperfusion remains ill-defined. Therefore the aim of the present study was to investigate the occurrence of oxidative stress in humans undergoing liver resection. Liver biopsies, and arterial and hepatic venous blood samples were taken from ten patients undergoing hepatectomy with an intermittent Pringle manoeuvre. Plasma MDA (malondialdehyde) and hepatic GSSG levels were measured as markers of oxidative stress and plasma uric acid as a marker of xanthine oxidase activity. In addition, changes in hepatosplanchnic consumption of plasma antioxidants and hepatic levels of carotenoids and glutathione (GSH) were measured. After ischaemia, hepatosplanchnic release of MDA and increased hepatic GSSG levels were found. This was accompanied by the release of uric acid, reflecting xanthine oxidase activity. During reperfusion, ongoing oxidative stress was observed by further increases in hepatic GSSG content and hepatosplanchnic MDA release. Uric acid release was minimal during reperfusion. A gradual decrease in plasma antioxidant capacity and net hepatosplanchnic antioxidant uptake was observed upon prolonged cumulative ischaemia. Oxidative stress occurs during hepatic ischaemia in man mainly due to xanthine oxidase activity. Interestingly, the gradual decline in plasma antioxidant capacity and net hepatosplanchnic antioxidant uptake during prolonged cumulative ischaemia, preserved both hydrophilic and lipophilic hepatic antioxidant levels. Decreasing plasma levels and net hepatosplanchnic uptake of plasma antioxidants may warrant antioxidant supplementation, although it should be clarified to what extent limitation of oxidative stress compromises ROS-dependent pathways of ischaemic preconditioning.

Topics: Aged; Antioxidants; Female; Hepatectomy; Humans; Intraoperative Period; Liver; Liver Neoplasms; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Reperfusion Injury; Splanchnic Circulation; Uric Acid; Xanthine Oxidase

Tannic acid, present in almost every food derived from plants, has been widely investigated as a chemopreventive agent because, apart from its use as a food additive, pharmacological studies have demonstrated its many health-promoting properties. In this study, we show the modulatory effect of tannic acid on 2-acetylaminofluorene (2-AAF)-mediated hepatic oxidative stress and cell proliferation in rats. 2-AAF (50 mg/kg body weight) caused reduction in hepatic glutathione content and the activities of hepatic anti-oxidant enzymes and phase-II metabolizing enzymes with an enhancement of xanthine oxidase activity, lipid peroxidation and hydrogen peroxide content. 2-AAF treatment also induced serum oxaloacetate and pyruvate transaminase, lactate dehydrogenase and gamma-glutamyl transpeptidase. Treatment of rats orally with tannic acid (125 and 250 mg/kg body weight) resulted in significant recovery of hepatic glutathione content, antioxidant and phase-II metabolizing enzymes. Also, significant decreases in lipid peroxidation, xanthine oxidase, hydrogen peroxide generation and liver damage marker enzymes were observed. The antiproliferative efficacy of the tannic acid was also evaluated. The promotion parameters induced (ornithine decarboxylase activity and DNA synthesis) by 2-AAF administration in the diet with partial hepatectomy (PH) were also significantly suppressed, dose dependently, by tannic acid. Hence, we propose that tannic acid might suppress the promotion stage via inhibition of oxidative stress and polyamine biosynthetic pathway.

Topics: 2-Acetylaminofluorene; Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Cell Proliferation; Chemoprevention; DNA; Dose-Response Relationship, Drug; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hydrogen Peroxide; Lipid Peroxidation; Liver; Liver Neoplasms; Male; Ornithine Decarboxylase; Oxidation-Reduction; Random Allocation; Rats; Superoxide Dismutase; Tannins; Xanthine Oxidase

The water extracts of Cornus officinalis Sieb. et Zuce against hepatocellular carcinoma (HCC) was studied for its chemopreventive potential. Three HCC cell lines (HepG2, SK-Hep1 and PLC/PRF/5) and three leukemic cell lines (U937, K562 and Raji) were tested with XTT assay. Extracts of C. officinalis inhibited all these HCC cells and leukemic cells at a concentration of 100 microg/ml (P < 0.05) and was dose-dependent (P < 0.0001). P53 (P< 0.0001) and Ras (P = 0.001) significantly affected its activity against HCC. Extracts of C. officinalis also possessed the anti-oxidant activity through free radicals scavenging activity at a concentration of 50 microg/ml (P < 0.05). In summary, our experiment implied that C. officinalis might be a candidate for chemopreventive agent against HCC through the antioxidant and anti-neoplastic effects.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cornus; Drugs, Chinese Herbal; Humans; K562 Cells; Lipid Peroxidation; Liver; Liver Neoplasms; U937 Cells; Xanthine Oxidase

Resveratrol, present in grapes and other plants, is a polyphenolic compound with strong antioxidative activity. In our previous studies, we found that reactive oxygen species (ROS) accelerated the invasive capacity of a rat ascites hepatoma cell line of AH109A in culture and that resveratrol and resveratrol-loaded rat sera suppressed the ROS-potentiated invasion of the hepatoma cells. To study mechanisms by which resveratrol and its in vivo metabolite(s) suppress the invasion, we estimated intracellular peroxide level and expression of hepatocyte growth factor (HGF), a known cell motility factor, in AH109A cells. Exogenously added ROS promoted the intracellular peroxide level and the expression of HGF. Resveratrol and resveratrol-loaded rat sera canceled the rise in the peroxide level and HGF expression in ROS-stimulated tumor cells. These results suggest an involvement of the antioxidative property of resveratrol and sera from rats orally given resveratrol in their suppressive effects on ROS-potentiated invasion of AH109A cells.

Topics: Animals; Carcinoma, Hepatocellular; Free Radical Scavengers; Gene Expression; Hepatocyte Growth Factor; Hypoxanthine; Liver Neoplasms; Male; Neoplasm Invasiveness; Rats; Reactive Oxygen Species; Resveratrol; Stilbenes; Tumor Cells, Cultured; Xanthine Oxidase

Acute tumor lysis syndrome (ATLS), which occurs spontaneously, without cytotoxic therapy, is a rare condition. Spontaneous TLS (STLS) has been seen most commonly in lymphoma and leukemia. We report a series of 3 cases of STLS in patients with solid tumors who were hospitalized in our department during a 9-month period and suggest that STLS is probably more frequent than previously thought.

Topics: Adrenal Gland Neoplasms; Aged; Aged, 80 and over; Allopurinol; Bone Neoplasms; Colonic Neoplasms; Female; Fluid Therapy; Humans; Hydrogen-Ion Concentration; Liver Neoplasms; Male; Necrosis; Pheochromocytoma; Tomography, X-Ray Computed; Tumor Lysis Syndrome; Urine

Tumor lysis syndrome (TLS) is a potential complication in cancer therapy. It may occur in highly sensitive tumors, especially in childhood cancers and acute leukemias, whereas it is rare in the treatment of adult solid tumors. TLS is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia following massive lysis of malignant cells. Complications include acute renal failure and metabolic acidosis. We report the first case of TLS during chemotherapy in a patient with metastatic medulloblastoma, together with a review of the literature regarding the occurrence of TLS in patients with solid tumors.. Data regarding clinical and biochemical parameters were extracted from the actual patients' files. Reports of TLS in the English language literature up to 2002 were identified by searching Medline.. A 23-year old male with metastatic medulloblastoma received chemotherapy with cisplatin and etoposide due to massive extracerebral manifestations including metastases to the liver, mediastinal lymph nodes and bone marrow metastases. The patient developed classical signs of TLS on the second day of chemotherapy, including acute renal failure. A 17-fold increase in plasma LDH up to 87608 U/l was observed together with a 4-fold increase in plasma creatinine. The patient was treated with aggressive hydration, allopurinol and repeated hemodialysis. During the following days the patient improved and the biochemical markers all returned to normal. REVIEW. Reviewing the literature, a total of 45 patients with solid tumors who developed TLS have been reported. Most of the patients presented with metastatic, therapy-sensitive disease. Although preventable in practically 100% of patients, TLS is a potentially fatal complication, and in this material the mortality rate was one in three. Risk factors included increased LDH, hyperuricemia and pretreatment azotemia.. TLS is only rarely associated with treatment of solid tumors. Precautions should be taken to avoid this potentially fatal complication in (chemo)therapy of solid tumors, especially in therapy-sensitive tumors presenting with bulky, metastatic disease and preexisting risk factors, including azotemia, elevated LDH and hyperuricemia. Prophylactic treatment to avoid TLS includes allopurinol, hydration prior to treatment and alkalization of the urine. Urate oxidase (rasburicase) is now beginning to replace allopurinol as a more effective way of reducing hyperuricemia and thereby the risk of TLS.

Topics: Adult; Allopurinol; Antimetabolites; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Cisplatin; Etoposide; Fluid Therapy; Humans; Liver Neoplasms; Male; Medulloblastoma; Renal Dialysis; Tumor Lysis Syndrome

The aim of this study was to investigate the level and the form of xanthine oxidoreductase (XOR) in severely diseased human livers, to ascertain whether the modifications of the enzyme activity reported in experimental pathology also occur in human liver disease.. Total, dehydrogenase, and oxidase activities of XOR were measured in samples of human liver removed for transplantation or partial hepatectomy. Samples included four groups: 1) histologically normal liver tissue, adjacent to metastases from extrahepatic tumors (controls), 2) liver with virus-related cirrhosis; 3) liver with virus-negative cirrhosis, and 4) hepatocellular carcinoma tissue (HCC).. The level of total XOR was significantly higher in liver with virus-related cirrhosis, but not in virus-negative cirrhosis, than in controls. In virus-positive cirrhosis, the total XOR activity correlated positively with the level of ALT. The percentage of XOR oxidase activity in cirrhotic liver, regardless of virus infection, correlated positively with aspartate amino-transferase, bilirubin concentration, and partial thromboplastin time, and negatively with prothrombin time. The activity of XOR was significantly lower in HCC than in control tissue or in a nonneoplastic area of the same liver.. Consistent with previous reports in experimental pathology, the level of XOR was increased in cirrhotic liver, in association with viral infection. This increment correlated with ALT, suggesting a relationship between XOR activity and the extent of liver injury caused by viral replication. The percentage of oxidase activity seems to be correlated with tissue damage and consequent liver impairment. The low XOR activity observed in HCC is consistent with reported experimental pathology.

Topics: Adult; Aged; Analysis of Variance; Biomarkers; Carcinoma, Hepatocellular; Female; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Xanthine Dehydrogenase; Xanthine Oxidase

Resveratrol, found in grapes, is a phytoalexin with antioxidative activity. The compound (100 and 200 microM) inhibited the proliferation of hepatoma cells, although this phytoalexin exerted little influence up to 50 microM. Resveratrol, however, suppressed the invasion of the hepatoma cells even at a concentration of 25 microM. Sera from rats orally given resveratrol restrained only the invasion of AH109A cells. Resveratrol and resveratrol-loaded rat serum suppressed reactive oxygen species-potentiated invasive capacity. These results suggest that the anti-invasive activity of resveratrol is independent of the anti-proliferative activity, and that the antioxidative property of resveratrol may be involved in its anti-invasive action.

Topics: Animals; Antineoplastic Agents; Antioxidants; Carcinoma, Hepatocellular; Cell Division; Hypoxanthine; Liver Neoplasms; Neoplasm Invasiveness; Rats; Resveratrol; Stilbenes; Tumor Cells, Cultured; Xanthine Oxidase

Tumour necrosis factor alpha (TNF-alpha) at 20 ng/ml induced apoptosis in human hepatoma cells in vitro. The effect of TNF-alpha-induced apoptosis was exacerbated by the hypoxanthine-xanthine oxidase (HX/XO) system and cycloheximide (CHX), but alleviated by superoxide dismutase (SOD), suggesting that TNF-alpha-induced apoptosis may be due to oxidative stress, and independent of protein synthesis. TNF-alpha elevated free Ca(2+)concentration, triggered lipid peroxidation and decreased the expression of bcl-2 protein. The findings suggest that TNF-alpha-induced apoptosis may be involved in stimulating Ca(2+)-dependent endonuclease activity and increasing membrane lipid peroxidation. Bcl-2 may play a pivotal role in serving as a Ca(2+)regulator or antioxidant, preventing lipid peroxidation in the process.

Topics: Acridine Orange; Apoptosis; Calcium; Carcinoma, Hepatocellular; Cycloheximide; Flow Cytometry; Humans; Hypoxanthine; Lipid Peroxidation; Liver Neoplasms; Oxidative Stress; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; Xanthine Oxidase

Serum concentration of thiobarbituric acid (TBA) reactants in the hepatic vein were measured before and after transient dearterialization of the liver in five human subjects bearing unresectable hepatocellular carcinoma (HCC). During 1 hour of the occlusion of the hepatic artery, change in TBA reactants level was slight. However, the mean value of TBA reactants in 1 hour after the reflow increased to 1.50 +/- 0.11 nmol/ml (mean +/- S.E.) and was significantly higher (p < 0.05) than those before hepatic dearterialization (1.28 +/- 0.11 nmol/ml) and just before the release of occlusion (1.32 +/- 0.09 nmol/ml). Further, two endogeneous scavenger enzymes, superoxide dismutase (SOD) and catalase (CAT), and one of the major sources of oxygen free radicals, xanthine oxidase (XOD) were measured in human untreated HCC and the corresponding adjacent liver tissue. The results demonstrated an increase in SOD in 81.8% (9/11) of HCC, and a decrease in CAT in 72.7% (8/11) of HCC when compared with the corresponding adjacent liver tissue. The mean value of SOD in HCC was significantly higher (66.8 +/- 6.5 vs 52.8 +/- 3.8 U/mg protein; p < 0.05), and that of CAT was significantly lower (22.6 +/- 2.4 vs 36.0 +/- 6.1 U/mg protein; p < 0.05) than those in liver tissue. All of nine HCC samples had a significantly lower activity of XOD (6.4 +/- 1.9 vs 20.3 +/- 3.4 pmol/minute/mg protein; p < 0.01) than the corresponding liver tissue. There was no obvious relation between the content of SOD and CAT in HCC, or in liver tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Carcinoma, Hepatocellular; Catalase; Female; Free Radicals; Humans; Ischemia; Liver; Liver Circulation; Liver Neoplasms; Male; Middle Aged; Oxygen; Reactive Oxygen Species; Reperfusion; Superoxide Dismutase; Thiobarbiturates; Xanthine Oxidase

Topics: Adenosine; Allopurinol; Blood Loss, Surgical; Constriction; Embolism, Air; Follow-Up Studies; Glutathione; Hepatectomy; Hepatic Veins; Humans; Hypothermia, Induced; Insulin; Ischemia; Ligation; Liver Circulation; Liver Diseases; Liver Failure; Liver Neoplasms; Organ Preservation Solutions; Perfusion; Portal Vein; Raffinose; Survival Rate; Time Factors; Tissue Preservation; Vena Cava, Inferior

Topics: 5'-Nucleotidase; Adenine Phosphoribosyltransferase; Adenosine Deaminase; Carcinoma, Hepatocellular; Cell Line; Culture Media; Cytosol; Guanine Deaminase; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Liver; Liver Neoplasms; Purine-Nucleoside Phosphorylase; Tumor Cells, Cultured; Xanthine; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Carcinoma, Hepatocellular; Culture Media, Conditioned; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Liver Neoplasms; Oxidation-Reduction; Purines; Tumor Cells, Cultured; Xanthine Oxidase; Xanthines

The NO-releasing compounds 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1), sodium nitroprusside (SNP) and S-nitroso-N-acetyl-DL-penicillamine (SNAP) mediated a rapid loss of viability of Fu5 rat hepatoma cells. SIN-1 in addition to NO also released the superoxide anion radical (O2-.). Its cytotoxicity, however, was not affected by superoxide dismutase. In contrast, the H2O2-converting enzyme catalase significantly, but not completely, diminished cell damage, indicating participation of H2O2 in the tumoricidal activity of SIN-1. Glucose oxidase (5 m-units/ml), producing similar amounts of H2O2 to 5 mM SIN-1, had no effect on cell viability. When 5 m-units/ml glucose oxidase was added to incubations with 5 mM SNP, which alone initiated cell injury of about 40%, cell damage was significantly increased up to 95%. Similar results were observed with 1 mM SNAP and 20 m-units/ml xanthine oxidase, which mediated cytotoxicity of about 90% when both compounds were added together, compared with 35% and 55% cell injury, respectively, induced by the single compounds. The results indicate that a co-operative action with H2O2 enhances the tumoricidal activity of NO in Fu5 cells. No evidence for an interplay of NO with O2-. in cytotoxicity, e.g. via the peroxynitrite anion (ONOO-), was found.

Topics: Animals; Carcinoma, Hepatocellular; Catalase; Cell Line; Cell Survival; Glucose Oxidase; Hydrogen Peroxide; Kinetics; Liver Neoplasms; Molsidomine; Nitric Oxide; Nitroprusside; Penicillamine; Rats; S-Nitroso-N-Acetylpenicillamine; Superoxide Dismutase; Superoxides; Tumor Cells, Cultured; Vasodilator Agents; Xanthine Oxidase

Topics: Adenoma, Bile Duct; Adenosine; Adult; Allopurinol; Bile Duct Neoplasms; Carcinoma, Hepatocellular; Colonic Neoplasms; Duodenal Neoplasms; Duodenum; Female; Glutathione; Humans; Insulin; Intestine, Small; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Organ Preservation; Organ Preservation Solutions; Pancreas Transplantation; Pancreatic Neoplasms; Raffinose; Solutions

Older patients with type I glycogen storage disease (GSD) develop hepatic adenomas that may undergo malignant transformation. Despite their similarity to oral contraceptive-related hepatic tumors, only one previous report has even mentioned hemorrhage in GSD-related hepatic tumors. We recently followed a 20-year-old patient with type Ia GSD and a 10 cm focal defect in the left lobe of the liver; angiography suggested that this was a benign adenoma. At 22 years of age, after an acute symptomatic episode, repeat studies (ultrasonography and angiography) revealed a 2 cm increase in diameter of the hepatic mass. Imminent tumor rupture was of grave concern; thus the patient was admitted to the hospital and given 2 weeks of constant glucose administration by central venous line in the hope of improving her metabolic abnormalities. After resolution of the coagulopathy and metabolic disorders, the patient safely underwent surgical enucleation of the tumor. Pathologic examination of the tumor revealed that the patient had indeed hemorrhaged into a typical hepatic adenoma that had focuses of hepatocellular dysplasia. She has done well without evidence of tumor recurrence for 3 years since the operation. We conclude that hemorrhage and malignant transformation are potential complications of GSD-related hepatic adenomas. This conclusion underscores the importance of following these patients closely as they age. Nocturnal nasogastric feeding should be considered in the hope of preventing a tumor or inducing regression. Acute symptomatic attacks should be evaluated promptly for possible tumor hemorrhage.

Topics: Adenoma; Adolescent; Adult; Allopurinol; Child; Follow-Up Studies; Glucose; Glycogen Storage Disease Type I; Hemorrhage; Humans; Infant; Infusions, Parenteral; Liver Diseases; Liver Neoplasms; Time Factors

Topics: Allopurinol; Biopsy, Needle; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Glycogen Storage Disease; Hemangiosarcoma; Hemochromatosis; Hepatitis, Alcoholic; Hepatitis, Chronic; Humans; Leprosy; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Liver Neoplasms; Peliosis Hepatis

Injection s.c. of purine 3-oxide into Wistar rats resulted in the appearance of sarcomas and fibromas at the interscapular site of administration, carcinomas in the liver, and a high incidence of s.c. fibromas in the hip at a distance from the site of injection. A small number of liver tumors but not tumors at the injection site appeared in rats to which the parent compound, purine, was administered. Oxidation of purine 3-oxide by xanthine oxidase was found to occur in two steps to yield the potent oncogen 3-hydroxyxanthine. A similar process may occur in vivo since a protein preparation from rat s.c. tissue has similar oxidizing activity.

Topics: Animals; Carcinogens; Carcinoma, Hepatocellular; Connective Tissue; Cyclic N-Oxides; Fibroma; Hypoxanthines; Injections, Subcutaneous; Liver Neoplasms; Male; Neoplasms, Experimental; Purines; Rats; Soft Tissue Neoplasms; Xanthine Oxidase

Cells from a rat hepatoma grown in culture were found to activate methyldopa to intermediates which are bound irreversibly to cellular proteins. The binding reaction was not inhibited by superoxide dismutase or allopurinol, but was strongly inhibited by ascorbic acid and glutathione. Methyldopa, paracetamol and furosemide were not mutagenic in the Salmonella/mammalian-microsome mutagenicity test.

Topics: Acetaminophen; Allopurinol; Animals; Ascorbic Acid; Carcinoma, Hepatocellular; Cells, Cultured; Deferoxamine; Dimethylnitrosamine; Edetic Acid; Furosemide; Glutathione; Liver Neoplasms; Maleates; Methyldopa; Neoplasms, Experimental; Protein Binding; Rats; Superoxide Dismutase; Time Factors; Xanthines

Topics: Adenine Phosphoribosyltransferase; Animals; Carcinoma, Hepatocellular; Cell Division; Female; Guanine Deaminase; Hypoxanthine Phosphoribosyltransferase; Liver; Liver Neoplasms; Liver Regeneration; Male; Neoplasms, Experimental; Purine-Nucleoside Phosphorylase; Purines; Rats; Rats, Inbred ACI; Rats, Inbred BUF; Time Factors; Xanthine Oxidase

Topics: Amidophosphoribosyltransferase; Animals; Carcinoma, Hepatocellular; Cell Division; Cell Transformation, Neoplastic; Female; Genes; IMP Dehydrogenase; Inosine Monophosphate; Inosine Nucleotides; Ligases; Liver; Liver Neoplasms; Liver Regeneration; Lyases; Male; Models, Biological; Neoplasms, Experimental; Pregnancy; Purines; Rats; Urate Oxidase; Xanthine Oxidase

The behavior of the rate-limiting enzyme of purine catabolism, xanthine oxidase (EC 1.2.3.2); was examined in normal liver, in 17 hepatomas of different growth rates, and in rapidly growing differentiating and regenerating liver. Xanthine oxidase activity was measured in the supernatant fluid prepared by centrifugation of 5% homogenates at 100,000 X g for 30 min. There was no uricase activity in the supernatant fluid. The affinity of xanthine oxidase to xanthine was similar in normal liver and in slow- and rapidly growing hepatomas (Km=6 to 8 muM), and theoptimum pH was 8.0; at pH 7.4, the activity was 80% of that at the pH optimum. A standard assay was worked out for the liver and hepatoma systems; the enzyme activity was linear during 60-min incubation and proportionate with amounts of protein added over a range of 0.5 to 3.0 mg. Xanthine oxidase specific activity was 9 times higher in small intestine than in liver. Activities in lung, spleen, kidney, heart, testes, and thymus were 67, 59, 21, 19, 8, and 8%, and in skeletal muscle, brain, and bone marrow activities were 5% of that of the liver. In regenerating liver, xanthine oxidase activity was not changed from that of the liver of sham-operated controls up to 96 hr after operation. The activity of the average differentiating liver cell was less than 5% of that of adult liver during the first week after birth. At postnatal ages of 18, 25, 30 and 40 days, the activity rose to 18, 46, 76, and 94%, respectively, of that of the adult liver. In starvation, hepatic xanthine oxidase activity per cell was preferentially depleted as compared to the decline in protein concentration. Upon refeeding, the enzymatic activity was restored more slowly than the protein content. Since xanthine oxidase activity was decreased in all examined hepatomas, including the slowest-growing, well-differentiated neoplasms, the altered activity of this enzyme appears to be.linked with neoplastic transformatiobosyl 1-pyrophosphate amidotransferase (EC 2.4.2.14), was increassed in the hepatomas, the reprogramming of gene expression results in an imbalance that favors the synthetic over the catabolic potential. This enzymatic imbalance should confer selective advantages to the cancer cells.

Topics: Animals; Carcinoma, Hepatocellular; Cell Differentiation; Cell Division; Cell Transformation, Neoplastic; Female; Genes; Intestine, Small; Kinetics; Liver; Liver Neoplasms; Liver Regeneration; Male; Neoplasms, Experimental; Pregnancy; Purines; Rats; Rats, Inbred ACI; Rats, Inbred Strains; Starvation; Xanthine Oxidase

Xanthine oxidase was decreased 2- to 10-fold in all examined rat hepatomas irrespective of the malignancy; growth rate and degrees of histological differentiation of the neoplasms. The affinity to substrate (KM=6-8 muM) and the pH optimum (8.0) of the liver and hepatoma enzymes were the same. The reprogramming of gene expression, as manifested in the decreased activity of this key purine metabolizing enzyme, appears to be specific to neoplastic transformation. Since glutamine PRPP amidotransferase activity was increased but the opposing enzyme, xanthine oxidase, was decreased in all the hepatomas, the reprogramming of gene expression results in an imbalance that favors synthesis against catabolism. This enzymatic imbalance should confer selective advantages to the cancer cells.

Topics: Age Factors; Animals; Carcinoma, Hepatocellular; Liver; Liver Neoplasms; Liver Regeneration; Male; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Xanthine Oxidase

Mitochondria from beef heart, Morris hepatoma 3924A and Ehrlich ascites tumor (Lettré mutant) have been studied with respect to hydrogen peroxidase and superoxide radical formation and the presence of superoxide dismutase activity (EC 1.15.1.1, superoxide:superoxide oxidoreductase). The generation of superoxide radicals and hydrogen peroxide occurs at the level of the membrane, being present also in mitochondrial fragments. Hepatoma and ascites mitochondria have little or no superoxide dismutase activity. Superoxide radicals appear to be precursors of hydrogen peroxide formation, the reaction being catalyzed by superoxide dismutase.

Topics: Animals; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Cattle; Free Radicals; Hydrogen Peroxide; Hydrogen-Ion Concentration; Kinetics; Liver Neoplasms; Mice; Mitochondria; Mitochondria, Muscle; Myocardium; Neoplasms, Experimental; Organ Specificity; Rats; Superoxide Dismutase; Superoxides; Xanthine Oxidase

Serum xanthine oxidase activity was measured by a radiochemical method in 137 consecutive patients with jaundice of varying etiology and in 40 non-jaundiced patients with liver or other disease. Serum xanthine oxidase was markedly increased, up to 50 times the upper normal limit (mean + 2 S.D.), in 32 out of 34 patients with infectious hepatitis. A slight elevation of serum xanthine oxidase, up to twice the upper normal limit, was found in 2 out of 49 patients with extrahepatic obstructive jaundice and in 4 out of 20 patients with chronic renal failure. In comparison to serum glutamic-oxaloacetic transaminase and lactate dehydrogenase serum xanthine oxidase appeared to be the more sensitive and specific indicator of acute hepatocellular damage.

Topics: Aspartate Aminotransferases; Chronic Disease; Hepatitis A; Humans; Jaundice; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Liver Cirrhosis; Liver Neoplasms; Myocardial Infarction; Neoplasm Metastasis; Xanthine Oxidase

Topics: Adenocarcinoma; Adult; Allopurinol; Antineoplastic Agents; Calcium; Cyclophosphamide; Fluorouracil; Humans; Hypercalcemia; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms; Plicamycin; Vincristine

Topics: Allopurinol; Animals; Carbon Radioisotopes; Carcinoma, Hepatocellular; Cells, Cultured; Clone Cells; Culture Media; Cycloheximide; Glycine; Growth; Hypoxanthines; In Vitro Techniques; Indicators and Reagents; Kinetics; Liver Neoplasms; Male; Pentosyltransferases; Purines; Pyrazoles; Pyrimidines; Rats; Ribonucleotides; Tritium; Xanthine Oxidase

Topics: Anemia; Animals; Chickens; Liver; Liver Neoplasms; Lymphoma; Neoplasm Transplantation; Poultry Diseases; Transplantation, Homologous; Uric Acid; Xanthine Oxidase

Topics: Age Factors; Animals; Aspartate Carbamoyltransferase; Carcinoma, Hepatocellular; Crosses, Genetic; Deoxyribonucleases; Female; Fructose; Fructose-Bisphosphatase; Glucose-6-Phosphatase; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Ribonucleases; Rodent Diseases; Xanthine Oxidase

Topics: Alkylation; Allopurinol; Blood Proteins; Carbon Isotopes; Cyclophosphamide; Feces; Half-Life; Humans; Kidney Failure, Chronic; Liver Neoplasms; Neoplasms; Nitrobenzenes; Prednisolone; Protein Binding; Pyridines; Time Factors; Ultrafiltration

Sequential studies on levels of glycogen and lactic acid as well as activities of glucose-6-phosphatase, fructose-1, 6-diphosphatase aldolase, aspartic and ornithine transcarbamylase, arginase and xanthine oxidase were carried out in liver and tumour tissue of mice fed with 0.03% thioacetamide in normal stock diet. It was observed that significant decrease in glycogen content and activities of gluconeogenic enzymes was apparent at the age of 4 months, i.e. 2 months after thioacetamide treatment. Alterations in the other parameters studied were observed later, i.e. at the age of 9 months. Maximum changes were observed in the hepatomas, i.e. at the age of 17 months.

Topics: Amides; Animals; Arginase; Carcinoma, Hepatocellular; Fructose-Bisphosphatase; Fructose-Bisphosphate Aldolase; Glucose-6-Phosphatase; Lactates; Liver; Liver Glycogen; Liver Neoplasms; Male; Mice; Neoplasms, Experimental; Ornithine Carbamoyltransferase; Sulfhydryl Compounds; Transferases; Xanthine Oxidase

Activities of glucose-6-phosphatase, fructose 1,6-diphosphatase, ornithine transcarbamylase, arginase and xanthine oxidase were measured in thioacetamide induced primary hepatoma and its tumour cell suspension. It was observed that the percentage decrease in the activities of all the enzymes in tumour cell suspension was far more than that observed in tumour tissue. However, in these studies no qualitative difference was observed between the parenchymal cells and the tumour cells.

Topics: Amides; Animals; Arginase; Carcinoma, Hepatocellular; Fructose-Bisphosphatase; Glucose-6-Phosphatase; In Vitro Techniques; Liver; Liver Neoplasms; Male; Mice; Neoplasms, Experimental; Ornithine Carbamoyltransferase; Sulfhydryl Compounds; Xanthine Oxidase

Topics: Allantoin; Allopurinol; Animals; Body Weight; Carbon Isotopes; Carcinoma, Hepatocellular; Diet; Enzymes; Growth; Hypoxanthines; In Vitro Techniques; Kidney; Liver; Liver Neoplasms; Male; Neoplasms, Experimental; Nucleosides; Rats; Spleen; Xanthine Oxidase; Xanthines

Topics: Adenosine; Aminohydrolases; Growth; Hepatectomy; Hypertrophy; Liver; Liver Neoplasms; Nucleosides; Phosphotransferases; Rats; Research; Transferases; Xanthine Oxidase

Topics: Adenosine Deaminase; Amidohydrolases; Humans; Liver Neoplasms; Neoplasms; Oxidoreductases; Phosphorylases; Xanthine Oxidase