Hepatotoxicity of fluorouracil with N-phosphonacetyl-L-aspartate.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
U Stenram
Publications and source records attributed to U Stenram.
Effect of biliary decompression on reticuloendothelial function in jaundiced rats.
The recovery of reticuloendothelial system (RES) function following decompression of obstructive jaundice was studied using a rat model with bile duct ligation and side-to-side choledochoduodenostomy. Histopathological changes in the liver were still present 5 weeks after relief of jaundice, while results of liver function tests had returned to normal. RES function evaluated by the blood clearance and organ uptake of radiolabelled Escherichia coli using a corrected phagocytic index gradually returned to normal following biliary decompression. The severely impaired RES activity noted 1 week after operation may explain the increased incidence of sepsis and renal insufficiency in the early period after biliary surgery in jaundiced patients.
Animals↗
Incorporation of 5-fluorouracil into rat liver tumor and normal tissues and the liver nucleotide profile after administration by the hepatic artery during portal venous branch ligation.
A therapeutic dose of labelled 5-fluorouracil (5-FU) was infused via the hepatic artery during 30 min with or without ligation of the left portal venous branch in Wistar rats with a secondary liver cancer in the left lateral lobe. After another 60 min, the incorporation of 5-FU into the acid soluble fraction (ASF), ribonucleic acid (RNA) and deoxyribonucleic acid (DNA), was determined in tumor, ligated and unligated liver lobes, small intestine, kidney, and bone marrow. The liver nucleotide profile was examined with isotachophoresis. Portal venous branch ligation (PVBL) caused the following changes, compared with the unligated control group: in the tumor, the incorporation of 5-FU into RNA and DNA decreased and the ratio RNA/acid-soluble fraction labelling decreased. The incorporation increased in intestinal and bone marrow RNA. It was unchanged in liver and kidney. The ratio of tumor to peripheral normal-tissue (small intestine, bone marrow, and kidney) labelling of RNA and DNA decreased. Liver nucleotides (F)UTP, (F)UDP-glucuronic acid, (F)UDP-N-acetylhexosamine, and NAD were lower in the ligated than in the unligated liver lobe. ATP and energy charge did not decrease significantly. In conclusion, PVBL in conjunction with hepatic arterial administration of 5-FU increased systemic drug exposure and possibly decreased hepatic tumor anabolism. It has not been examined how this interferes with the therapeutic effect.
Animals↗
Immunohistochemical characterization of endocrine cells in experimental exocrine pancreatic cancer in the Syrian golden hamster.
Fifty exocrine pancreatic adenocarcinomas and 57 benign tumors induced in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) were examined for the presence of argyrophil cells antiinsulin, -glucagon, -somatostatin, -pancreatic polypeptide (PP), -gastrin/CCK, -vasoactive intestinal polypeptide (VIP), and - neuron-specific enolase (NSE) reactive cells. Argyrophil - and antihormone-reactive cells were found in the normal pancreatic ducts and in the acini, as well as in hyperplastic and atypical ducts/ductules, tubular complexes, benign lesions, and in 80% of ductal adenocarcinomas. Insulin and antiNSE-reactive cells were the most common, followed in decreasing frequency by glucagon, somatostatin, and PP cells. Antigastrin-/CCK-and -VIP-reactive cells were found in two cases. Argyrophil cells were present in about 60% of the tumors with Grimelius staining and in 55% of those with Churukian-Schenk staining. Insulin cells were seen in ductal cancer that had grown into a lymph node and in the lymph node metastases of another cancer. A novel finding was the presence of argyrophil and insulin cells within the lumen of some malignant glandular structures. Coexistence of several peptide cells was found in 52% of the cancers. The presence of argyrophil and hormone-producing cells in induced pancreatic ductal/ductular lesions further strengthens the existence of a close developmental relationship between exocrine and endocrine cells of the pancreas.
Adenocarcinoma↗
Immunohistochemical studies of beta-hexosaminidase in neoplastic and normal tissues with monoclonal antibodies.
A total of 87 human specimens with 10 histological types of primary neoplasm were studied immunohistochemically with monoclonal antibodies specific for beta-hexosaminidase (Hex). High levels of Hex were found in malignant neoplasms of the skin, cervix, colorectum and in benign as well as neoplastic plasma cells, while no activity was detected in normal epidermis, normal colorectal epithelium or benign naevi. The strongest immunohistochemical reaction was revealed in tumor cells of malignant melanoma. Adenomas and adenocarcinomas of the colorectum showed high levels of Hex with a basal pattern of immunoreactivity more frequent in the tumor cells of adenocarcinomas than adenomas. Fibroblasts and macrophages in the tumors often disclosed immunoreactivity. In most of the sections (including those from plasma cell neoplasms), 7E4 antibody showed low immunoreactivity compared to 2E3, except for non-neoplastic plasma cells, which were as a rule positive with 7E4 and largely negative with 2E3 antibody. This result probably indicated different isoenzymes in benign and neoplastic plasma cells.
Adenoma↗
The influence of biliary obstruction and sepsis on reticuloendothelial function in rats.
Obstructive jaundice is frequently associated with septic complications and renal impairment. The present study was performed in order to evaluate reticuloendothelial system (RES) function in obstructive jaundice and the influence of a septic challenge. Male Sprague-Dawley rats were allocated into four groups (laparotomy alone, caecal ligation and puncture (CLP), ligation of the common bile duct (CBD) alone and CBD+CLP, respectively). Mortality, blood clearance and organ distribution of 125I labelled Escherichia coli were determined. Mortality in sepsis (CLP) significantly increased in jaundiced animals (p less than 0.033). Blood clearance of radiolabelled E. coli was significantly impaired in both jaundiced groups. In jaundiced animals, hepatic localisation and renal uptake of E. coli significantly increased (p less than 0.001), while radioactive counts in bile significantly decreased (p less than 0.01). Changes in organ distribution of bacteria did not depend on alterations in blood flow. Thus, RES function was impaired in jaundiced animals and mortality increased in a concomitant septic challenge in jaundiced animals.
Animals↗
Reduction by norepinephrine of the side effects induced by combined hepatic arterial administration of degradable strach microspheres and adriamycin in rats with a liver adenocarcinoma.
In previous studies we found degradable starch microspheres (DSM) to increase the antitumor effect of adriamycin injected by the hepatic artery in rats with a liver adenocarcinoma. Increased side effects also appeared, namely body weight loss and liver necroses. In the present paper, norepinephrine in four different protocols was added to the injection of adriamycin + DSM to decrease the drug flow to normal tissues. In two protocols norepinephrine decreased the body weight loss. There was also a non-significant decrease in liver necroses but also in antitumor effect. In these experiments we also observed that some rats given adriamycin + DSM got gastric necroses. This was not found when norepinephrine was added. Addition of propranolol to norepinephrine did not decrease side effects. Vasoactive drugs may therefore be of value to diminish adverse side effects of the combination cytostatic agent + DSM, probably decreasing overspill into normal tissues.
Adenocarcinoma↗
beta-hexosaminidase in cultured normal and mutant human fibroblasts: an immunohistochemical and biochemical investigation.
Fibroblasts from a genetically normal individual and mutant fibroblasts from patients with Tay-Sachs and Sandhoff's diseases were grown in vitro. The lysosomal enzyme beta-hexosaminidase (Hex) was determined biochemically and localized with monoclonal antibodies recognizing Hex A, and Hex A and Hex B, respectively. The biochemical results showed similar amounts of Hex A and Hex B in the normal fibroblasts, whereas only Hex B activity was detectable in the fibroblasts from the patient with Tay-Sachs disease. The fibroblasts from the patient with Sandhoff's disease showed small amounts of Hex A- and no Hex B activity. Immunohistochemically, Hex was detectable with both antibodies in the normal fibroblasts and in those from the patient with Tay-Sachs disease. The fibroblasts from the patient with Sandhoff's disease were reactive only with Hex A-specific antibody.
Cell Line↗
Sclerotherapy for ablation of the gallbladder after gallstone lithotripsy with a mechanical lithotriptor. An experimental study in pigs on the effect of absolute ethanol on edematous gallbladder wall.
Chemical ablation of the gallbladder with absolute ethanol following mechanical lithotripsy with the RotoLith lithotriptor was attempted in 10 pigs after open cholecystostomy. Two gallbladders removed immediately after the sclerotherapy demonstrated extensive ulcerations of the mucosa with preserved glands and sinuses under the ulcerations. In 8 gallbladders removed 8 weeks after sclerotherapy a gallbladder remnant with hydrops and/or mucus and more or less intact epithelium was seen in all the pigs. In order to prevent regeneration of epithelium from gallbladder sinuses and glands, more effective sclerosing agents must be found.
Animals↗
Nucleotide profile in rat liver and intestine at portal vein obstruction and reflow.
Liver and intestinal nucleotides and energy charge levels were examined in rats at portal vein clamping for 1, 5 or 30 min and after reflow for 1 or 6 h following 30 min clamping. In both tissues, clamping resulted in a loss of ATP, energy charge, UTP, GTP, UDP-glucuronic acid and UDP-N-acetylhexosamine levels, which all, except ATP and total adenosine phosphates, essentially recovered at 1 h reflow. At 6 h reflow, liver UDP-glucuronic acid and liver glutathione decreased in both clamped and sham operated rats.
Animals↗
Methodological approaches to immunohistochemical demonstration of beta-hexosaminidase in human placental and renal tissue with monoclonal antibodies.
The lysosomal enzyme, beta-hexosaminidase (Hex), was studied in full-term human placentas and in renal tissue using monoclonal antibodies raised against Hex purified from human placentas. The immunohistochemical reaction for Hex was pronounced in trophoblastic cells and macrophages of the basal plate and the smooth chorion, but was faint or negative in the amnion as well as in the syncytiotrophoblast and Hofbauer cells of the chorionic villi. The maternal decidual cells of the basal plate were negative. Biochemical enzyme analysis showed the highest activity in basal plate cells (containing trophoblast, decidual cells, macrophages and neutrophils) and a low activity in the chorionic villi. Placental tissue was less positive with monoclonal antibodies specific for Hex A, compared with antibodies reacting with both Hex A and Hex B. Epithelial cells of the renal proximal tubules were positive to the same degree with antibodies recognizing both Hex A and Hex B as well as those recognizing only Hex A.
Antibodies, Monoclonal↗
The incorporation of 5-fluorouracil into rat liver tumor and normal tissues after administration by the hepatic artery during temporary portal vein clamping.
A therapeutic dose of labelled 5-fluorouracil (5-FU) was infused via the hepatic artery during 30 min with or without a simultaneous temporary clamping of the portal vein in a model of secondary liver cancer in Wistar rats. After another 60 min, the incorporation of 5-FU into the acid soluble fraction, RNA and DNA was determined in tumor, liver, small intestine, kidney, and bone marrow. The liver and intestinal nucleotide profiles were examined with isotachophoresis. Temporary portal vein clamping caused the following changes, as compared with the control group with intraarterial infusion only: in the liver, the incorporation of 5-FU into the acid soluble fraction increased without a concomitant increase into the RNA or of the level of (F)UTP. Liver ATP decreased. In the tumor, the ratio of RNA to acid soluble fraction labelling decreased. There was a generally decreased ratio of tumor to peripheral normal tissue (small intestine and kidney) labelling. In conclusion, portal vein clamping in conjunction with hepatic arterial administration of 5-FU led to a decreased anabolism of 5-FU in the liver and tumor, and increased systemic drug exposure. It is not known how this interferes with the therapeutic effect.
Adenosine Triphosphate↗
Time-resolved laser-induced fluorescence spectroscopy for enhanced demarcation of human atherosclerotic plaques.
We report on the enhanced demarcation between human atherosclerotic plaques and normal vessel wall obtained using time-resolved detection of laser-induced fluorescence rather than the customary time-integrated monitoring technique. A frequency-doubled mode-locked and cavity-dumped continuous wave dye laser was used for picosecond pulse generation at 320 nm, and photon-counting techniques were employed for the time-resolved signal monitoring from human aorta samples in vitro. Implications for imaging fluorescence angioscopy and spectroscopic guidance in laser ablation of plaque are indicated.
Aorta↗
Decrease of liver energy charge, ATP and glutathione at concomitant intraarterial administration of adriamycin and degradable starch microspheres in rat.
Adriamycin (Adr) and degradable starch microspheres (DSM) were infused either combined or each separately into the hepatic artery in rats. Liver ATP, GTP, UDP-glucuronic acid, UDP-N-acetyl-hexosamine and energy charge and glutathione were decreased 20 min later with combined treatment but not by Adr or DSM when infused alone. the nucleotide levels were normalized 60 min after the combined treatment. After one week, the Adr rats showed a less weight gain than controls. The Adr + DSM rats lost weight. Only minor changes were found in the livers at microscopical examination at this time.
Adenosine Triphosphate↗
Enhanced effect of adriamycin on a rat liver adenocarcinoma after hepatic artery injection with degradable starch microspheres.
Rats with solitary liver tumors were treated with adriamycin administered via the hepatic artery with and without degradable starch microspheres. Tumor growth inhibition was significantly greater, and tumors were decreased in size 7 days after, following treatment with adriamycin + microspheres. The bone marrow seemed to be protected. However, the addition of microspheres to adriamycin gave a body weight loss and evidence of increased liver damage. Possible interrelations between liver damage, antitumor effect and body weight loss are indicated.
Adenocarcinoma↗
Immunohistochemical demonstration of beta-hexosaminidase in cirrhotic and cholestatic human livers with a monoclonal antibody.
The lysosomal enzyme beta-hexosaminidase (Hex) was studied immunohistochemically with a monoclonal antibody in normal human livers and in livers with cirrhosis and cholestasis. No reaction was detected in sections from normal livers. The reaction in diseased livers was prominent mainly in degenerating hepatocytes, whereas Kupffer cells and bile duct epithelium showed faint reactivity. The reaction product was intense in degenerated hepatocytes, especially in the periphery of the pseudolobules in cirrhotic livers. In cholestatic livers the positivity was localized around central veins in cells with bile pigment. The more pigment, the stronger was the reaction. It is suggested that the elevated level of serum Hex found in cirrhosis and cholestasis derives from degenerating hepatocytes and activated Kupffer cells.
Antibodies, Monoclonal↗
Effects of dosage and infusion time on the incorporation of 5-fluorouracil into DNA and RNA of normal tissues and an adenocarcinoma transplanted to rat liver.
In a model of secondary liver cancer in Wistar rats the incorporation of 5-FUra into the acid soluble fraction, RNA, and DNA of several normal tissues and of an adenocarcinoma of the colon transplanted to the liver was determined; 300, 1,200 or 24,000 nmoles of 5-FUra were infused via the gastroduodenal artery for 0.5, 2, or 24 hr. The rats were killed 1.5, 3, or 24 hr after the beginning of the infusions. In general, higher doses resulted in a higher labelling. However, the ratio of incorporation into tumor RNA compared to normal tissue RNA was higher at the 1,200 than at the 24,000 nmole dosage. There was a decreased RNA/DNA ratio in the tumor at 24 hr after 24,000 nmoles of 5-FUra had been infused over 0.5 or 2 hr, indicating decreased synthesis and/or increased breakdown of RNA.
Adenocarcinoma↗
Splenic and gastro-duodenal vein occlusion--influence on the pancreatic gland and on the outcome of experimental pancreatitis.
The observation that splenic vein thrombosis results in pancreatic changes similar to haemorrhagic pancreatitis initiated the present investigation. The influence of splenic and/or gastroduodenal vein occlusion on the pancreatic gland was evaluated and compared to that obtained after induction of experimental pancreatitis (EP). The influence of splenic vein occlusion on EP was also investigated. An approximately 4-fold increase in serum amylase activity was obtained after simultaneous ligation of the splenic and gastroduodenal veins. This increase was comparable to that obtained after EP. On the other hand, amylase activity in ascites was considerably lower after vein occlusion than after EP. Splenic vein occlusion in rats with EP more moderately increased the amylase activity but did not influence mortality rate 24 h postoperatively. Venous thromboses were observed in all groups with occluded veins but not in rats with EP. Vein occlusion alone did not result in fat necroses. Although occlusion of the splenic and gastroduodenal veins results in macromorphologic and biochemical changes resembling those in EP, the microscopic findings of the two conditions differ. Thus, the results do not support the hypothesis that pancreatic vein thromboses are of etiologic significance for the development of acute haemorrhagic pancreatitis.
Amylases↗