PubMed Health⌕ Search

Biomedical subjects

J S Holcenberg

Publications and source records attributed to J S Holcenberg.

At least 55 records · Page 3Linked to original sources
PubMed1984

Effect of asparaginase on cell membranes of sensitive and resistant mouse lymphoma cells.

High concentrations of Escherichia coli asparaginase (80 U/ml) altered the binding of concanavalin A (Con A) to L 5178Y murine lymphoma cells that are sensitive to the cytotoxic action of this enzyme. Incubation of the asparaginase sensitive line in asparagine-free media or media containing Acinetobacter glutaminase-asparaginase did not alter the Con A binding of these cells. Escherichia coli asparaginase had no effect on Con A binding of two asparaginase resistant L5178Y cell lines that were isolated and maintained in asparagine depleted or asparaginase containing medium. The E. coli asparaginase preparation inhibited protein and glycoprotein biosynthesis to comparable degrees. It did not have proteolytic or glycolytic activity. Escherichia coli asparaginase did not alter the binding of wheat germ, soybean or ricin agglutinins to any of these cell lines. These data suggest that high concentrations of E. coli asparaginase have a specific effect on the Con A receptor in the sensitive line.

Amino Acids↗
PubMed1984

Effects of single-dose and fractionated cranial irradiation on rat brain accumulation of methotrexate.

The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same wether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation.

Animals↗
PubMed1983

Successful long-term use of a plasmapheresis reactor system in dogs with lymphoma.

The successful long-term use of asparaginase-glutaminase reactor in dogs with lymphoma is described. The limitations of the system consisting of an activation of enzymes leading to rapid neosynthesis of asparagine and glutamine are outlined. The possible beneficial effect of future combination therapy with amino acid analogues is discussed.

Animals↗
PubMed1982

Sensitivity of cultured pancreatic carcinoma cells to Acinetobacter glutaminase-asparaginase.

Cultured human pancreatic carcinoma cells (MIA PaCa-2) have been shown previously to be very sensitive to E. coli L-asparaginase (EC II). The present studies have demonstrated that another enzyme, Acinetobacter glutaminase-asparaginase (AGA) is much more effective in inhibiting cell growth. At the concentration of 0.0025 U/ml of AGA activity the enzyme totally inhibited cell growth, whereas the EC II with the same concentration did not show any effect. The inhibition of cell growth correlated well with inhibition of protein and glycoprotein synthesis. The addition of L-glutamine at the concentration of 1 mM completely reversed the inhibition of protein synthesis. Similarly, the addition of L-glutamine at the concentration of 3 mM daily on 3 successive days after adding AGA resulted in significant reversal of growth inhibition. The results of this study indicate that the action of AGA on MIA PaCa-2 is, to a great extent, exerted through its L-glutaminase activity.

Acinetobacter↗
PubMed1981

L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans.

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were measured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of 111In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 +/- 0.7 (S.D.) hr versus 5.8 +/- 0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-asparaginase. Similar results were found in seven patients undergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF asparagine in both species was 0.1 IU/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-asparaginase.

Animals↗
PubMed1981

Levels of 2'-deoxycoformycin, adenosine, and deoxyadenosine in patients with acute lymphoblastic leukemia.

2'-Deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase, has recently undergone Phase I clinical trials and has been found to be therapeutically active in acute lymphoblastic leukemia. In this report, levels of dCF in plasma, plasma concentrations of adenosine and deoxyadenosine, and urine levels of deoxyadenosine were measured in leukemic patients undergoing treatment with dCF during a Phase I clinical trial. dCF was administered i.v. at a dose of 0.25 to 1.0 mg/kg (7.5 to 30 mg/sq m) for 3 consecutive days. Plasma drug levels of 2 to 6 microM were observed following the third dose of dCF, and drug accumulation occurred only at the 1-mg/kg dosage. In this limited series of patients, the plasma concentrations of adenosine and deoxyadenosine and the urine concentrations of deoxyadenosine did not show an obvious correlation with dCF dose, therapeutic response, or toxicity.

Adenosine↗
PubMed1981

Amino acid utilization and urine protein excretion in children treated with succinylated Acinetobacter glutaminase-asparaginase.

Amino acid utilization was evaluated in seven children with acute lymphocytic leukemia treated with succinylated Acinetobacter glutaminase-asparaginase. All patients received food p.o. ad libitum and glucose-electrolyte solutions i.v.; four patients received an i.v. amino acid supplement (1.5 g/kg/day). Although all patients were in negative energy balance, there was a significant linear regression between nitrogen balance and nitrogen intake during Days 1 to 7 and Days 8 to 14 of the study. The slope of the regression line, reflecting exogenous nitrogen utilization, was not significantly different from that found in healthy young men ingesting adequate or subadequate energy intakes. The Y-intercept (-210 mg/kg/day) indicated an obligatory nitrogen loss that was much greater than normal. Most of the nitrogen loss was due to urinary excretion. Ammonia and urea accounted for 77 to 91% of the urine nitrogen. Urinary glutamate accounted for 4 to 10% of this loss. Urine protein excretion was abnormally high in each of the patients, ranging from 987 to 3440 mg/day. Urine excretion of N-acetyl-beta-glucosaminidase and beta 2-microglobulin was also abnormally high, despite normal blood urea nitrogen and serum creatinine, suggesting that these children had renal tubular dysfunction. The antileukemic effect of succinylated Acinetobacter glutaminase-asparaginase did not appear to be altered by amino acid supplementation. These data indicate that amino acid supplementation can improve nutritional status in patients treated with succinylated Acinetobacter glutaminase-asparaginase.

Acetylglucosaminidase↗
PubMed1981

Nitrogen utilization in mice bearing Ehrlich ascites tumor treated with Acinetobacter glutaminase-asparaginase.

The effects of Acinetobacter glutaminase-asparaginase (AGA) on protein and energy requirements were evaluated in mice bearing Ehrlich ascites tumors. In an initial experiment with normal mice, a zero protein diet resulted in a significant decrease in carcass nitrogen, liver nitrogen, and carcass energy relative to the animals on a normal, low, or high protein diet. In a second experiment, mice bearing Ehrlich ascites tumors were randomized into diet groups (zero or normal protein) and treatment groups (daily injections of AGA or 0.9% NaCl solution). In both treatment groups, the zero protein diet resulted in significant decreases in weight, liver nitrogen, carcass nitrogen, and carcass energy. Neither tumor nor AGA treatment affected body composition or the efficiency of nitrogen utilization. By Day 8, either the zero protein diet or AGA treatment significantly reduced ascites volume and tumor nitrogen content relative to controls. In a modification of Experiment 2, AGA treatment was stopped on Day 8, and all animals were given a normal protein diet. AGA, but not the zero protein diet, significantly enhanced ultimate survival. These experiments indicate that the requirements and utilization of energy and nitrogen are normal in mice with Ehrlich ascites tumor whether or not they are treated with AGA.

Acinetobacter↗
PubMed1981

The bio-artificial organ: review and progress report.

A definition and a review is given for the bioartificial organ. In addition new developments are reported with the successful lyophilization of enzyme filled RCG with cryoprotective polyethylene glycol (PEG). The successful use of an enzyme reactor consisting of crosslinked fibrin with asparaginase covalently attached is reported in sheep. The small organ (0.4 m2) removes 70% of the animal's asparagine in 6 hours. No enzyme leakage down to 10(-5) units per ml. plasma could be found. The highly preserved substrate affinity of insolubilized asparaginase as well as its high activity and stability when bound to fibrin are additional outstanding features of this system.

Animals↗
PubMed1981

Enzyme therapy of cancer, future studies.

The dramatic clinical responses to L-asparaginase led to renewed interest in other enzymes that might be effective antitumor agents. Biochemical and nutritional studies on animal and human tumors have shown that enzymatic depletion of glutamine, arginine, cysteine, citrulline, and serine could have selective cytotoxicity for some tumors. Several glutaminase-asparaginase enzymes have antitumor activity in animals and man. These enzymes are currently in phase I trials. Arginine-depleting enzymes with suitable properties of therapy have been developed and are in preclinical study. Enzymes have not yet been found that can adequately deplete circulating levels of cysteine, citrulline, or serine for treatment of cancer.

Adolescent↗
PubMed1980

Thyroid carcinoma following treatment for acute lymphoblastic leukemia.

A 2 1/2-year-old girl with acute lymphoblastic leukemia received chemotherapy and prophylactic cranial irradiation. After six years of remission, including three years off therapy, metastatic thyroid carcinoma appeared in the cervical lymph nodes. The predisposing factors for the development of thyroid carcinoma as a second malignancy in this case are discussed. It is suggested that thyroid carcinoma should be added to the growing list of second malignancies in acute lymphoblastic leukemia and that careful thyroid examination be included in the follow-up of long-term survivors.

Antineoplastic Agents↗