32 results on '"Zoltán A. Tökés"'
Search Results
2. Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome
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Margaret K. McCuskey, Zoltán A. Tökés, Xiangdong Wang, Jeffrey Tsai, Laurie D. DeLeve, Robert S. McCuskey, Nancy W. Bethea, Gary Kanel, and Yoshiya Ito
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Male ,Pathology ,medicine.medical_specialty ,Pyrrolidines ,Hepatic Veno-Occlusive Disease ,Biology ,Nitric Oxide ,Nitric oxide ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Sinusoid ,Internal medicine ,medicine ,Animals ,Viability assay ,Nitrites ,Diminution ,Nitrates ,Hepatology ,Liver cell ,Metalloendopeptidases ,Rats ,Endothelial stem cell ,Microscopy, Electron ,Endocrinology ,Liver ,chemistry ,Toxicity ,Perfusion - Abstract
This study examined the role of decreased nitric oxide (NO) in the microcirculatory obstruction of hepatic sinusoidal obstruction syndrome (SOS). SOS was induced in rats with monocrotaline. Monocrotaline caused hepatic vein NO to decrease by 30% at 24 hours and by 70% at 72 hours; this decrease persisted throughout late SOS. N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, exacerbated monocrotaline toxicity, whereas V-PYRRO/NO, a liver-selective NO donor prodrug, restored NO levels, preserved sinusoidal endothelial cell (SEC) integrity and sinusoidal perfusion as assessed by in vivo microscopy and electron microscopy, and prevented clinical and histologic evidence of SOS. NO production in vitro by SEC and Kupffer cells, the 2 major liver cell sources of NO, decreases largely in parallel with loss of cell viability after exposure to monocrotaline. Increased matrix metalloproteinase (MMP) activity increases early on in SOS and this increase in activity has been implicated in initiating SOS. Infusion of V-PYRRO-NO prevented the monocrotaline-induced increase in MMP-9. In conclusion, decreased hepatic NO production contributes to the development of SOS. Infusion of an NO donor preserves SEC integrity and prevents development of SOS. These findings show that a decrease in NO contributes to SOS by allowing up-regulation of MMP activity, loss of sinusoidal integrity, and subsequent disruption of sinusoidal perfusion.
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- 2003
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3. Matrix Metalloproteinases in the Neocortex and Spinal Cord of Amyotrophic Lateral Sclerosis Patients
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Carol A. Miller, Giselle P. Lim, Jon R. Backstrom, Roscoe Atkinson, Zoltán A. Tökés, and Michael Cullen
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Male ,Pathology ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,alpha 1-Antichymotrypsin ,Blotting, Western ,Gelatinase A ,Central nervous system ,Biochemistry ,Cellular and Molecular Neuroscience ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Aged ,Aged, 80 and over ,Cerebral Cortex ,Motor Neurons ,Neocortex ,business.industry ,Amyotrophic Lateral Sclerosis ,Metalloendopeptidases ,Anatomy ,Middle Aged ,Motor neuron ,Spinal cord ,medicine.disease ,Immunohistochemistry ,Extracellular Matrix ,medicine.anatomical_structure ,Spinal Cord ,Female ,business ,Motor cortex ,Astrocyte - Abstract
Matrix metalloproteinases (MMPs) were analyzed by immunohistochemistry and zymography in amyotrophic lateral sclerosis (ALS) and control brain and spinal cord specimens. Three major bands of enzyme activity (70, 100, and 130 kDa) were consistently observed and were subsequently identified as MMP-2 (70 kDa; also known as EC 3.4.24.24 or gelatinase A) and MMP-9 (100 and 130 kDa; also known as EC 3.4.24.35 or gelatinase B). Immunohistochemical studies established the presence of MMP-2 in astrocytes and MMP-9 in pyramidal neurons in the motor cortex and motor neurons in the spinal cord of ALS patients. Although a significant decrease in MMP-2 activity was noticed in the ALS motor cortex, statistically significant increases in MMP-9 (100-kDa) activity were observed in ALS frontal and occipital cortices (BA10 and 17) and all three spinal cord regions when compared with control specimens. The highest MMP-9 (100-kDa) activities in ALS were found in the motor cortex and thoracic and lumbar cord specimens. The abnormally high amount of MMP-9 and its possible release at the synapse may destroy the structural integrity of the surrounding matrix, thereby contributing to the pathogenesis of ALS.
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- 2002
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4. Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents
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Patricia Bonaz-Krause, Kenichi Komatsu, Yegor Zyrianov, Csaba Csipke, Zoltán A. Tökés, Charles E. McKenna, Eric J. Lien, Rubin Wang, and Shijun Ren
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Quantitative structure–activity relationship ,Schiff base ,Stereochemistry ,Quantitative Structure-Activity Relationship ,Antineoplastic Agents ,Chemical synthesis ,Acid dissociation constant ,Semicarbazides ,Partition coefficient ,chemistry.chemical_compound ,Mice ,chemistry ,Drug Discovery ,Tumor Cells, Cultured ,Molecular Medicine ,L1210 cells ,Animals ,Humans ,Drug Screening Assays, Antitumor ,Leukemia L1210 ,IC50 ,Semicarbazone ,Schiff Bases - Abstract
Thirty Schiff bases of hydroxysemicarbazide (Ar-CH=NNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC(50) values were found to be in a range from 2.7 x 10(-6) to 9.4 x 10(-4) M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC(50) values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC(50) = 8.2 x 10(-5) M). The partition coefficient (log P) and ionization constants (pK(a)) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch-Fujita pi constant of -CH=NNHCONHOH. On the basis of the newly derived pi and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of pi values. Quantitative structure-activity relationship (QSAR) analysis showed that, besides the essential pharmacophore (-NHCONHOH), hydrophobicity (SlogP), molecular size/polarizability (calculated molar refractivity), and the presence of an oxygen-containing group at the ortho position (I) were important determinants for the antitumor activities. In conclusion, the results obtained in this study show that several Schiff bases of hydroxysemicarbazide are potent inhibitors of tumor cells and warrant further investigation as cancer chemotherapeutic agents.
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- 2002
5. Matrix metalloproteinases in dog brains exhibiting Alzheimer-like characteristics
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Giselle P. Lim, Zoltán A. Tökés, Michael J. Russell, and Michael Cullen
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Male ,medicine.medical_specialty ,Central nervous system ,Hippocampus ,Matrix metalloproteinase ,Biology ,Hippocampal formation ,Biochemistry ,Cellular and Molecular Neuroscience ,Enzyme activator ,Dogs ,Alzheimer Disease ,Internal medicine ,mental disorders ,medicine ,Animals ,Humans ,Zymography ,Collagenases ,Aged ,chemistry.chemical_classification ,Aged, 80 and over ,Brain Chemistry ,Molecular mass ,Enzyme Activation ,Enzyme ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Matrix Metalloproteinase 9 ,Gelatin ,Female - Abstract
We have previously reported that the amount of the neuronal matrix metalloproteinase (MMP) MMP-9, capable of cleaving beta-amyloid,-40 predominantly at Leu34-Met35, is increased in a latent form in hippocampal specimens from AD patients and have suggested that the lack of activation of this enzyme may contribute to the deposition of beta-amyloid in plaques. The current study addresses whether similar matrix proteinases are detectable in amyloid-positive and -negative brain specimens of aged beagles. Using quantitative zymography, three major neutral proteinases with molecular masses of 60, 95, and 280 kDa were readily detected. These enzymes have the characteristics of MMPs because they were inhibited by EDTA and 1, 10-phenanthroline, and their activities were restored by addition of both Ca2+ and Zn2+. The 95- and 280-kDa proteinases cross-reacted with specific monoclonal antibodies to human MMP-9 (gelatinase B; EC 3.4. 24.35). Canine MMP-9 was latent because activation by organomercurial treatment resulted in a characteristic decrease in molecular mass. Statistical analysis revealed no difference in the 60-kDa proteinase activity in amyloid-positive and -negative brain specimens. However, significantly increased amounts of latent MMP-9 were observed in amyloid-positive brain specimens (p < or = 0.05) compared with amyloid-negative brain specimens. The observations document that changes in MMP-9 expression in amyloid-positive beagle brains are similar to those reported in the human Alzheimer's disease hippocampus and suggest the possibility that insufficient activation of MMP-9 may contribute to beta-amyloid accumulation, a hypothesis that needs to be further investigated.
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- 1997
6. Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1-40)
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Michael Cullen, Giselle P. Lim, Zoltán A. Tökés, and Jon R. Backstrom
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Adult ,Male ,Transcription, Genetic ,Amyloid beta ,Molecular Sequence Data ,Peptide ,Biology ,Matrix metalloproteinase ,Hippocampus ,Polymerase Chain Reaction ,Enzyme activator ,Alzheimer Disease ,Reference Values ,Extracellular ,Humans ,Amino Acid Sequence ,Collagenases ,RNA, Messenger ,Peptide sequence ,Aged ,chemistry.chemical_classification ,Aged, 80 and over ,Neurons ,Amyloid beta-Peptides ,General Neuroscience ,Articles ,Middle Aged ,Molecular biology ,Enzyme assay ,Peptide Fragments ,Enzyme ,chemistry ,Matrix Metalloproteinase 9 ,biology.protein ,Immunologic Techniques ,Female - Abstract
We reported earlier that the levels of Ca2+-dependent metalloproteinases are increased in Alzheimer’s disease (AD) specimens, relative to control specimens. Here we show that these enzymes are forms of the matrix metalloproteinase MMP-9 (EC3.4.24.35) and are expressed in the human hippocampus. Affinity-purified antibodies to MMP-9 labeled pyramidal neurons, but not granular neurons or glial cells. MMP-9 mRNA is expressed in pyramidal neurons, as determined with digoxigenin-labeled MMP-9 riboprobes, and the presence of this mRNA is confirmed with reverse transcriptase PCR. The cellular distribution of MMP-9 is altered in AD because 76% of the total 100 kDa enzyme activity is found in the soluble fraction of control specimens, whereas only 51% is detectable in the same fraction from AD specimens. The accumulated 100 kDa enzyme from AD brain is latent and can be converted to an active form with aminophenylmercuric acetate.MMP-9 also is detected in close proximity to extracellular amyloid plaques. Because a major constituent of plaques is the 4 kDa β-amyloid peptide, synthetic Aβ1–40was incubated with activated MMP-9. The enzyme cleaves the peptide at several sites, predominantly at Leu34-Met35within the membrane-spanning domain. These results establish that neurons have the capacity to synthesize MMP-9, which, on activation, may degrade extracellular substrates such as β-amyloid. Because the latent form of MMP-9 accumulates in AD brain, it is hypothesized that the lack of enzyme activation contributes to the accumulation of insoluble β-amyloid peptides in plaques.
- Published
- 1996
7. The 84-kDa form of human matrix metalloproteinase-9 degrades substance P and gelatin
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Zoltán A. Tökés and Jon R. Backstrom
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Tachykinin peptides ,Molecular Sequence Data ,Substance P ,Peptide ,In Vitro Techniques ,Biochemistry ,Cell Line ,Substrate Specificity ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Gelatinase ,Humans ,Amino Acid Sequence ,Collagenases ,chemistry.chemical_classification ,Enzyme Activation ,Molecular Weight ,Kassinin ,Kinetics ,Enzyme ,chemistry ,Matrix Metalloproteinase 9 ,Gelatin ,Neurokinin A ,Neurokinin B - Abstract
Matrix metalloproteinase-9 (MMP-9) is secreted from cells and, once activated, is thought to degrade collagen in the extracellular matrix. Because collagen is not readily localized where neurons have been shown to produce MMP-9 in the human brain, the ability of this enzyme to degrade bioactive peptides was investigated with representative tachykinin peptides [substance P (SP), neurokinin A, neurokinin B, and kassinin]. Latent MMP-9 (94 kDa) was purified from the human cell line HL-60 and converted to an intermediary active form (84 kDa) with p-aminophenylmercuric acetate. This active form of MMP-9 degraded SP with a k cat /K m of 170 m M -1 min -1 , which is 30-fold greater than the previously reported value for a representative collagen-derived peptide. The major digestion products were identified as SP 1-6 and SP 7-11 , which were derived from cleavage of the Gln 6 -Phe 7 bond. Minor products were also generated from cleavage of the Gly 9 -Leu 10 bond. The other representative tachykinin peptides were cleaved at rates >10-fold slower than that of SP. The 84-kDa peptidase was also active as a gelatinase. Longer treatment of MMP-9 with p-aminophenylmercuric acetate caused the conversion of the 84-kDa enzyme to the established 68-kDa active form; however, the rate of SP degradation did not increase. Because MMP-9 is produced by neurons of the CNS, these results suggest a possible regulatory role for the enzyme in intercellular communication by altering the availability of bioactive peptides
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- 1995
8. Characterization of neutral proteinases from Alzheimer-affected and control brain specimens: identification of calcium-dependent metalloproteinases from the hippocampus
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Jon R. Backstrom, Zoltán A. Tökés, and Carol A. Miller
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Male ,Sodium ,chemistry.chemical_element ,Hippocampal formation ,Calcium ,Matrix metalloproteinase ,Biochemistry ,Hippocampus ,Substrate Specificity ,Cellular and Molecular Neuroscience ,Enzyme activator ,Alzheimer Disease ,Reference Values ,Casein ,Endopeptidases ,Humans ,Aged ,Gel electrophoresis ,Aged, 80 and over ,Brain ,Metalloendopeptidases ,Middle Aged ,Molecular biology ,Enzyme Activation ,chemistry ,Specific activity - Abstract
Three neutral proteinases from human hippocampal tissue have been identified and partially characterized using substrate gel electrophoresis. The proteinases showed activity when gelatin was used as the substrate, but had no detectable activity against casein. Based on the results of inhibition studies and the calcium requirements, it was concluded that the activities were due to calcium-dependent metalloproteinases. The apparent molecular weights were 130,000 (MP-130), 100,000 (MP-100), and 70,000 (MP-70). Half-maximal activities were observed with 20 microM Ca2+ for MP-130, 40 microM Ca2+ for MP-100, and 800 microM Ca2+ for MP-70. In the presence of Ca2+, Zn2+ reestablished the activities of the three metalloproteinases at a lower concentration than did either Co2+ or Mn2+. One millimolar Al3+ inhibited 67% of the MP-70 activity, but did not affect the MP-100 and MP-130 activities. An analysis of Alzheimer-affected hippocampal and control samples showed that the specific activity (in units per milligram of sodium dodecyl sulfate-soluble protein) of MP-70 varied less than the activities of MP-100 and MP-130 between the two groups. Although p-amino-phenylmercuric acetate (p-APMA) increased the activities of MP-70 by 70% in both groups of specimens, the resulting activities from Alzheimer samples were greater than those from control samples (p less than 0.01). A wide range of MP-100 specific activity was observed in both groups, and its mean activity was higher in Alzheimer-affected samples (p less than 0.05). Treatment with p-APMA increased the activity of MP-100 only 25% in both groups of tissue samples. MP-130 activity was detected predominantly in Alzheimer-affected hippocampal specimens, and treatment with p-APMA failed to increase its activity in both the control and the Alzheimer-affected specimens. The results demonstrate an elevated level of metalloproteinase activities, capable of degrading tissue matrix components, in the hippocampus from postmortem Alzheimer patients.
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- 1992
9. Phenotypic variations dictate the intracellular compartmentalization of doxorubicin in normal human bone marrow cells
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Zoltán A. Tökés and Esther Aghaï
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Cancer Research ,Pathology ,medicine.medical_specialty ,Cytoplasm ,Reticulocytes ,Drug Resistance ,Biology ,In Vitro Techniques ,Toxicology ,Bone Marrow ,Reference Values ,medicine ,Humans ,Pharmacology (medical) ,Doxorubicin ,Pharmacology ,Cell Nucleus ,Macrophages ,Compartmentalization (psychology) ,In vitro ,Chromatin ,Cell biology ,Cell Compartmentation ,Haematopoiesis ,Cell nucleus ,medicine.anatomical_structure ,Phenotype ,Oncology ,Microscopy, Fluorescence ,Cell culture ,Bone marrow ,Intracellular ,medicine.drug ,Granulocytes - Abstract
In vitro accumulation of doxorubicin in intracellular compartments of normal bone marrow cells was studied with the use of fluorescent microscopy. Both the cytoplasmic and nuclear compartments had distinguishable drug accessibility in the diverse hemopoietic series and in different stages of maturation of each lineage. Nuclei appeared to be more sheltered in the myelogranulogytic series and macrophages appeared to be the least Nuclei of activated phagocytic cells of the myelogranulocytic series and macrophages appeared to be the least accessible to doxorubicin uptake. These observations establish that phenotypic variations dictate the patterns of anthracyclines' subcellular compartmentalization. They also suggest that the molecular mechanism contributing to the intracellular trafficking of doxorubicin deserves more substantial investigation that may contribute to our understanding of drug resistance and sensitity.
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- 1990
10. Prevention of hepatic venoocclusive disease in the rat by inhibition of matrix metalloproteinases
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Jeffrey Tsai, Laurie D. DeLeve, Xiangdong Wang, Gary Kanel, and Zoltán A. Tökés
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Pathology ,medicine.medical_specialty ,Hepatology ,business.industry ,Venoocclusive disease ,Gastroenterology ,Medicine ,Matrix metalloproteinase ,business - Published
- 2001
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11. Synthesis of adriamycin-coupled polyglutaraldehyde microspheres and evaluation of their cytostatic activity
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Alan Rembaum, Kathryn E. Rogers, and Zoltán A. Tökés
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Binding Sites ,Multidisciplinary ,Cell Survival ,Cell Membrane ,Cell ,Biology ,Molecular biology ,Microspheres ,Cell membrane ,Membrane ,medicine.anatomical_structure ,Doxorubicin ,Glutaral ,Cell culture ,Drug delivery ,medicine ,Protein biosynthesis ,Animals ,Binding site ,Leukemia L1210 ,Cells, Cultured ,Research Article ,medicine.drug - Abstract
Adriamycin was coupled to polyglutaraldehyde microspheres having an average diameter of 4500 A. The coupled microspheres remained stable during incubation with cells. Full cytostatic activity was observed when the coupled adriamycin was tested with murine or human leukemia and murine sarcoma cell lines. A 10-fold increase in sensitivity was obtained with drug-resistant human leukemia cell lines. Repeated use of the coupled microspheres in the cytostatic assays did not increase their activity, indicating that these complexes can be recycled. The results suggest that coupled adriamycin sufficiently perturbs the plasma membrane to lead to cytostatic activity. It is proposed that this mode of drug delivery provides multiple and repetitious sites for drug-cell interactions. In addition, the drug-polymer complexes may overcome those forms of resistance that are the result of decreased drug binding at the cell surface.
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- 1982
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12. In vitro synthesis and secretion of glycoprotein by human mammary tissue
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Zoltán A. Tökés and Gerald B. Dermer
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Gel electrophoresis ,chemistry.chemical_classification ,Hyperplasia ,Golgi Apparatus ,Plant Science ,Biology ,Organ culture ,Molecular biology ,Epithelium ,Fucose ,In vitro ,Molecular Weight ,chemistry.chemical_compound ,Organ Culture Techniques ,Mammary Epithelium ,chemistry ,Biochemistry ,Glucosamine ,Humans ,Female ,Secretion ,Breast ,Glycoprotein ,Glycoproteins ,Biotechnology - Abstract
Organ cultures of human surgical specimens can be used to investigate glycoprotein production in vitro under conditions in which three-dimensional tissue structures and cell-cell interactions resemble those present in vivo. In this report, an organ-culture system is used to investigate the synthesis, transport and release of glycoprotein by normal and benign hyperplastic human mammary epithelium. Autoradiography of explants pulse-labeled with individual glycoprotein precursors ([3H]glucosamine, [3H]fucose, [3H]acetylmannosamine) and maintained in organ culture for intervals up to 72 hr revealed that glycoprotein is synthesized and then secreted by mammary epithelium. Incorporation of each isotope took place in the Golgi apparatus. Most of the newly synthesized glycoprotein, labeled with each of the three precursors, then was transported to apical cell surfaces and secreted into gland lumina. Observations were indistinguishable in normal and benign hyperplastic glands. Thus nonlactating human mammary epithelium exhibits a glycoprotein secretory activity. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [3H]glucosamine-labeled macromolecules released into the medium showed a group of glycoproteins with a molecular weight of 48,000 +/- 6,000 daltons plus high-molecular-weight glycosylated components at the top of gels. The nature of gp48 is not known, but similar molecular-weight glycoproteins also are released by surgical specimens of human mammary cancer maintained in organ culture.
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- 1978
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13. Immunohistochemical demonstration of proteinase inhibitor alpha-1-antichymotrypsin in normal human central nervous system
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Roy H. Rhodes, Deanna L. Justice, and Zoltán A. Tökés
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Pathology ,medicine.medical_specialty ,Ependymal Cell ,Central nervous system ,Cell Biology ,Anatomy ,Biology ,Biochemistry ,Epithelium ,medicine.anatomical_structure ,Cerebral cortex ,medicine ,Choroid plexus ,Neuron ,Ependyma ,Molecular Biology ,Immunostaining - Abstract
The presence of alpha-1-antichymotrypsin, a serine proteinase inhibitor with a high affinity for cathepsin G, is demonstrated in the normal human central nervous system (CNS) by immunohistochemical techniques. Paraffin-embedded normal human CNS tissue from five adult, two fetal, one neonatal and three newborn autopsies were stained with monospecific rabbit antibodies to human alpha-1-antichymotrypsin using biotinylated goat anti-rabbit antibodies and an avidin-biotin- peroxidase complex. Positive immunostaining was seen in neurons and glial cells in the cerebral cortex, basal ganglia, hippocampus, cerebellum, brainstem, and spinal cord of the adults. The epithelium of the adult choroid plexus had the most intense staining in apical granular organelles corresponding in position to lysosomes or secretory granules. Ependymal cells, particularly those near the choroid plexus, were immunostained. The fetal CNS had no alpha-1-antichymotrypsin staining. Limited staining of choroid plexus, ependyma. and frontal lobe was found in the newborns. Immunostaining in the neonatal temporal lobe was only found in the choroid-plexus epithelium. These observations establish a widespread distribution of this proteinase inhibitor in the normal human CNS. Developmental regulation of this inhibitor in the human CNS is also indicated.
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- 1987
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14. Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity
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Eric A. Forssen and Zoltán A. Tökés
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Anions ,Liposome ,Cardiotoxicity ,Multidisciplinary ,Anthracycline ,Leukemia P388 ,Vesicle ,Body Weight ,Heart ,Pharmacology ,Mice ,chemistry.chemical_compound ,chemistry ,Doxorubicin ,Phosphatidylcholine ,Injections, Intravenous ,Liposomes ,Toxicity ,medicine ,Animals ,Growth inhibition ,Leukemia L1210 ,Research Article ,medicine.drug - Abstract
Anionic liposomes containing doxorubicin were evaluated in mice for therapeutic potential in reducing the risks of chronic cardiotoxicity characteristic of long-term high-dose anthracycline therapy. Doxorubicin first was complexed to phosphatidylcholine and then entrapped in anionic vesicles. Quantitation of myocardial injury was accomplished through examination of thin sections of cardiac tissue by light microscopy. At treatment levels of either 20 or 40 mg/kg (total dose), mice receiving liposomal doxorubicin had toxicity scores indistinguishable from or only slightly greater than those of saline-treated controls. Similar total doses of free drug produced moderate to severe myocardial damage and yielded much higher toxicity scores. Mixture of free doxorubicin with empty liposomes did not alleviate cardiac toxicity, indicating that the drug must be entrapped within phospholipid vesicles for reduction in toxicity. The inhibition of body growth produced by free doxorubicin at both dose levels was also completely eliminated by encapsulation in liposomes. Doxorubicin liposomes were also tested for chemotherapeutic potential against L-1210 and P-388 murine leukemias. In all cases, treatment with liposomal doxorubicin produced increases in life-span greater than that observed for free drug. We conclude that anionic liposomes can function as efficacious carriers of doxorubicin. These vesicles possess improved therapeutic action as reflected by their ability to reduce cardiac toxicity, overcome growth inhibition, and increase antileukemic activity.
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- 1981
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15. Anchorage independent growth and plasminogen activator production by bovine endothelial cells
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William F. Benedict, Zoltán A. Tökés, Nino Sorgente, and Walter E. Laug
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Endothelium ,Cell division ,Fluorescent Antibody Technique ,Biology ,Plasminogen Activators ,Culture Techniques ,medicine ,Animals ,Neoplastic transformation ,Aorta ,Cell growth ,Sepharose ,Muscle, Smooth ,Articles ,Cell Biology ,Molecular biology ,Clone Cells ,Endothelial stem cell ,Agar ,medicine.anatomical_structure ,Karyotyping ,Cattle ,Anchorage-Independent Growth ,Plasminogen activator ,Cell Division ,Fibrinolytic agent - Abstract
Endothelial cells obtained from the aortae of 1- to 2-d-old calves were cloned at high efficiency using fibrin-coated dishes. Primary cultures as well as clones derived from them produced high fibrinolytic activity when grown on 125I-fibrin-coated dishes which was 90% dependent upon the presence of plasminogen. High plasminogen-dependent proteolytic activity was also demonstrated in endothelial cell lysates and in the culture medium of the cells. The production and secretion of the plasminogen activator(s) were found to increase during the log phase of cell growth and to reach a maximum level at confluence. These endothelial cells exhibited morphological phenotypes comparable to those of transformed cells when grown in the presence of acid-treated fetal calf, dog, or human serum. Furthermore, they demonstrated anchorage independent growth, and large colonies were formed in semisolid media. Spontaneous neoplastic transformation of these cells was excluded by karyotypic analysis, lack of tumorigenicity in athymic nude mice, and limited lifespan in culture. Cell clones isolated from colonies grown in agarose demonstrated the same growth characteristics and proteolytic activity as before plating in agarose. High fibrinolytic activity, morphological changes in the appropriate serum, and growth in semisolid media may therefore be indicative of the migratory and/or invasive capacity of both nontransformed endothelial cells as well as tumor cells.
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- 1980
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16. Cell surface-associated and released proteolytic activities of bovine aorta endothelial cells
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Nino Sorgente and Zoltán A. Tökés
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Proteases ,Cell Survival ,Cell ,Biophysics ,Peptide ,Biology ,Biochemistry ,medicine.artery ,Casein ,Monolayer ,medicine ,Animals ,Molecular Biology ,Aorta ,Cells, Cultured ,chemistry.chemical_classification ,Caseins ,Endothelial Cells ,Substrate (chemistry) ,Cell Biology ,Microspheres ,Cell biology ,Endothelial stem cell ,medicine.anatomical_structure ,chemistry ,Cattle ,Peptides ,Peptide Hydrolases - Abstract
We have demonstrated cell surface-associated and released proteolytic activity on bovine aorta endothelial cells, representing normal cells with regulated invasive properties. To demonstrate these proteolytic activities on viable cells grown in monolayer cultures, a new method was developed. The method consists of rolling modified plastic beads carrying covalently-linked [125I]-labeled casein in contact with the cell surfaces or adjacent to the cell monolayers without actual contact. The rate of radioactive peptide release is proportional to the proteolytic activity. Released proteases are detected when no contact occurs between the substrate and the cells. When the bead-substrate complex is rolled over the surface of endothelial cells, a significant increase in released labeled peptides is observed which represents a cell surface-associated proteolytic activity. These activities may be relevant to the endothelial cell's invasive capacity and appear to be similar to the neutral proteolytic activity of transformed cells.
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- 1976
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17. Proteolytic activity associated with human erythrocyte membranes. Self-digestion of isolated human erythrocyte membranes
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Zoltán A. Tökés and Susan M. Chambers
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Erythrocytes ,Isoflurophate ,Detergents ,Biophysics ,Biology ,Biochemistry ,Tosyl Compounds ,Cell membrane ,Aprotinin ,Casein ,Pepstatins ,medicine ,Humans ,Trypsin ,Spectrin ,Edetic Acid ,Glycoproteins ,chemistry.chemical_classification ,Latex beads ,Cell Membrane ,Caseins ,Blood Proteins ,Cell Biology ,Hydrogen-Ion Concentration ,Glutathione ,Kinetics ,Zinc ,Enzyme ,medicine.anatomical_structure ,Membrane ,chemistry ,Sulfonic Acids ,Digestion ,Peptide Hydrolases ,medicine.drug - Abstract
At least two kinds of enzymes are active in the proteolytic self-digestion of erythrocyte membranes. The specific activities of these enzymes do not decrease with repeated washings of purified stroma. The effects of a variety of inhibitors on the membrane preparation's capacity to digest 125-I-labelled casein, covalently linked to latex beads, have been examined. Pepstatin-inhibitable enzyme, active at low pH, digests the membrane extensively to small polypeptide fragments. Spectrin, located at the internal part of the membrane, is readily degraded. Diisopropylfluorophosphate-inhibitable enzyme, active at pH 8-9, has only limited digestive capacity. Some of the membrane components, such as the small molecular weight glycoproteins, are resistant to digestion. The restricted capacity of digestion is due to the membrane molecular arrangement; increased disaggregation removes the restriction and increases the activity. Spectrin is not digested unless the membrane topography is disrupted by NP-40 neutral detergent. These observations suggest that the enzymes active at basic pH are located external to the cell. Intact cells do possess a limited capacity to degrade 125-I-labelled casein when their surfaces are brought into contact with substrate-coated beads.
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- 1975
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18. Expression of an active proteinase inhibitor, α1-antichymotrypsin, by human breast epithelial cells
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Zoltán A. Tökés and Sandra J. Gendler
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alpha 1-Antichymotrypsin ,Biophysics ,Fluorescent Antibody Technique ,Breast Neoplasms ,Biology ,Biochemistry ,Epithelium ,Cell Line ,chemistry.chemical_compound ,Biosynthesis ,In vivo ,Cell Adhesion ,medicine ,Extracellular ,Chymotrypsin ,Humans ,Breast ,Isoelectric Point ,Molecular Biology ,Glycoproteins ,chemistry.chemical_classification ,Enzyme assay ,Molecular Weight ,medicine.anatomical_structure ,chemistry ,Cell culture ,biology.protein ,Female ,Glycoprotein - Abstract
The synthesis of an active proteinase inhibitor, gp 66, by human breast epithelial cells is reported. This glycoprotein is identical to serum α 1 -antichymotrypsin, which inhibits proteinases that cleave at hydrophobic residues. Immunohistological studies show the in vivo expression on normal secretory and ductal epithelial cells and on primary and metastatic adenocarcinomas. Immunoaffinity-purified gp 66 from MCF-7 culture supernatants is an active inhibitor of chymotrypsin as determined in a fluorogenic enzyme assay and can form stable 88 kDa enzyme-inhibitor complexes. The synthesis of a functional inhibitor may represent the epithelial cell's attempt to stabilize its extracellular milieu.
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- 1986
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19. Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of 2-hydroxy-1H-isoindolediones as new cytostatic agents
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Carcy L. Chan, Zoltán A. Tökés, and Eric J. Lien
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Quantitative structure–activity relationship ,Indoles ,Magnetic Resonance Spectroscopy ,Bicyclic molecule ,Stereochemistry ,Chemistry ,Cytostatic agents ,Substituent ,Antineoplastic Agents ,Nuclear magnetic resonance spectroscopy ,Inhibitory postsynaptic potential ,Mass Spectrometry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Molecular Medicine ,Structure–activity relationship ,Chromatography, Thin Layer ,Leukemia L1210 ,Imide - Abstract
A series of 16 derivatives of 2-hydroxy-1H-isoindole-1,3-diones was designed and synthesized as potential antitumor agents. The cytostatic activity against L1210 cell growth of these compounds was studied, and their IC50 values were found to be in the range of 10(-4) to 10(-8) M. Quantitative structure-activity relationship analysis of these compounds showed that the inhibitory effect was well correlated with the electronic and the lipophilic parameters. Derivatives having a substituent with strongly electron-donating properties at the 6-position showed enhanced inhibitory activity while compounds having an electron-withdrawing group at the same position showed lower activity.
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- 1987
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20. Liposome encapsulation enhancement of methotrexate sensitivity in a transport resistant human leukemic cell line
- Author
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Peter W. Rossow, Zoltán A. Tökés, John A. Todd, and Edward J. Modest
- Subjects
Pharmacology ,Drug ,Liposome ,Leukemia, Experimental ,Cholesterol ,media_common.quotation_subject ,Vesicle ,Mutant ,Drug Resistance ,Biological Transport ,Biochemistry ,Cell Line ,chemistry.chemical_compound ,Methotrexate ,chemistry ,Cell culture ,Liposomes ,medicine ,Animals ,Humans ,media_common ,medicine.drug ,Deficient cell - Abstract
A stable mutant of human leukemia CCRF/CEM cells has recently been isolated which is transport resistant for methotrexate (MTX). Encapsulation of MTX in cationic unilamellar liposomes increased the association of the drug 5-fold with the sensitive, and 50-fold with the resistant, cells as compared to the uptake of free drug. The liposome-mediated associations of MTX with sensitive and transport deficient cell lines were similar. Cytostatic studies demonstrated that liposome encapsulation increased MTX activity 4-fold towards the transport resistant cell line. The addition of cholesterol to the vesicles decreased their effectiveness. A 4-fold increase in drug sensitivity due to encapsulation may allow such transport resistant tumor cells to become responsive to chemotherapeutic doses of MTX which are currently feasible in human clinical protocols.
- Published
- 1982
21. Molecular Markers and the Manifestation of Metastasis
- Author
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Zoltán A. Tökés
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Lung metastasis ,medicine.disease ,Malignancy ,Treatment failure ,Metastasis ,Subcutaneous injection ,Breast cancer ,Internal medicine ,medicine ,Good prognosis ,business - Abstract
There are two ways to conceptualize tumor invasion and metastasis, which are the major causes of treatment failure for patients with malignancy. In one approach, the researcher classifies molecular or histological markers as manifestations of favorable factors. Such a conceptualization realizes that either the high expression of one set of parameters or the diminished presence of another set would suggest a low incidence of metastasis and good prognosis. The low efficiency of metastatic events would also be stressed. For example, an intravenous or subcutaneous injection of fifty-thousand mammary carcinoma cells into a Fisher rat (as in the case of experimental or spontaneous models for metastases) can result in fifty to a hundred colonies of lung metastasis. The experiment would be perceived as evidence for the rather low efficiency of metastatic success.
- Published
- 1986
- Full Text
- View/download PDF
22. Glycoprotein synthesis as a function of epithelial cell arrangement: biosynthesis and release of glycoproteins by human breast and prostate cells in organ culture
- Author
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Gerald B. Dermer and Zoltán A. Tökés
- Subjects
Male ,Estrogen receptor ,Breast Neoplasms ,Biology ,Adenocarcinoma ,Organ culture ,Epithelium ,Cell Line ,Organ Culture Techniques ,Prostate ,medicine ,Carcinoma ,Humans ,Breast ,Glycoproteins ,Gel electrophoresis ,chemistry.chemical_classification ,Prostatic Neoplasms ,General Medicine ,Hyperplasia ,medicine.disease ,Molecular biology ,medicine.anatomical_structure ,Carcinoma, Intraductal, Noninfiltrating ,chemistry ,Immunology ,Female ,Glycoprotein - Abstract
We demonstrate that a technique is available to investigate glycoprotein synthesis in organ cultures of human breast and prostate surgical specimens where the 3-dimensional epithelial cell arrangement remains intact. Malignant breast and prostate epithelium maintained their capacity to synthesize glycoproteins for at least 3 days as followed by the incorporation of [3H] glucosamine into macromolecules. Over 70% of incorporation was by malignant cells as judged by autoradiography. Labeled glycoproteins were released into glandular lumina and consequently into the culture fluid. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed predominantly one group of macromolecules released with an apparent molecular weight of 48,000 ± 6,000 daltons. This glycoprotein was found in all of the breast specimens studied, which included 1 medullary, 1 infiltrating lobular, and 8 infiltrating duct carcinomas. The pattern was independent of the availability of estrogen receptors. A similar glycoprotein was also observed in the culture media from a Grade I and a Grade II well-differentiated infiltrating prostate carcinoma. Incorporation was below the level of detection in 4 of 6 cases of benign prostatic hyperplasia. A more complex pattern of labeled glycoproteins was found in the media of a Grade II and a Grade III poorly-differentiated prostate carcinoma. The established human mammary carcinoma cell line MCF-7 synthesized and released a similar 48,000 molecular weight glycoprotein but additional components with larger molecular weights were also released. An intriguing interpretation that 3-dimensional tissue integrity restricts some glycorprotein synthesis is discussed. Cells grown in 2-dimensional monolayers could escape from such a topographic restriction and express additional families of glycoproteins.
- Published
- 1977
23. Neurotoxicity and dermatotoxicity of cyanomorpholinyl adriamycin
- Author
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Roy H. Rhodes, Edward M. Acton, Zoltán A. Tökés, and Steven C. Cramer
- Subjects
Cancer Research ,Ataxia ,Anthracycline ,Ratón ,Pharmacology ,Toxicology ,Fluorescence ,Mice ,Hypokinesia ,medicine ,Animals ,Distribution (pharmacology) ,Pharmacology (medical) ,health care economics and organizations ,Skin ,Cardiotoxicity ,Antibiotics, Antineoplastic ,business.industry ,Neurotoxicity ,Brain ,medicine.disease ,humanities ,Oncology ,Doxorubicin ,Anesthesia ,Toxicity ,medicine.symptom ,business - Abstract
The highly lipophilic cyanomorpholinyl adriamycin (CMA) is the most potent antineoplastic anthracycline yet described. CNS distribution and toxicity were examined after i.v. administration of CMA to mice. At doses greater than or equal to 0.1 mg/kg, a neurotoxic syndrome including ataxia, hypokinesia, and tremors appeared. At doses of less than or equal to 0.05 mg/kg, which have been reported to be antineoplastic, no neurotoxicity was observed. On histopathologic examination, no changes were observed in the brain, spinal cord, or dorsal root ganglia. Unlike adriamycin (ADR), which rapidly appears in the nuclei of several tissues, CMA showed no fluorescence, suggesting a different cellular microcompartmentalization. The i.d. injection of CMA disclosed a 200-fold increase in toxicity compared with that of adriamycin. In comparisons of CMA and ADR, neurotoxicity and cardiotoxicity occurred equally only at higher doses; however, the dermatotoxicity and antineoplastic activity of CMA were increased several hundred-fold.
- Published
- 1989
- Full Text
- View/download PDF
24. Liposome-Encapsulated Methotrexate Interactions With Human Chronic Lymphocytic Leukemia Cells<xref ref-type='fn' rid='FN2'>2</xref><xref ref-type='fn' rid='FN3'>3</xref>
- Author
-
John A. Todd, Alexandra M. Levine, and Zoltán A. Tökés
- Subjects
musculoskeletal diseases ,CD20 ,chemistry.chemical_classification ,Drug ,Cancer Research ,Liposome ,biology ,Chronic lymphocytic leukemia ,media_common.quotation_subject ,Pharmacology ,medicine.disease ,Enzyme ,Oncology ,chemistry ,In vivo ,Dihydrofolate reductase ,biology.protein ,medicine ,Methotrexate ,medicine.drug ,media_common - Abstract
The uptake of free and liposome-entrapped methotrexate (MTX) by human chronic lymphocytic leukemia cells was compared under incubation conditions resembling those encountered in vivo. Liposome encapsulation enhanced up to 200 times the association of MTX with these cells. Autoradiographic studies established an association of [3H]MTX liposomes with the cells. Such a mode of delivery did not significantly increase the amount of drug available to inhibit dihydrotolate dehydrogenase, which suggested that the liposome content was not readily available to the cytoplasmic sites of action. Increased doses of encapsulated MTX resulted in enzyme inhibitions that were similar to those obtained with the free drug. This finding demonstrates that higher doses of MTX delivered by liposomes could be potentially useful in overcoming drug-transport resistance.
- Published
- 1980
- Full Text
- View/download PDF
25. Evaluation of a Radioimmunoassay for α1-Acid Glycoprotein To Monitor Therapy of Cancer Patients<xref ref-type='fn' rid='FN2'>2</xref><xref ref-type='fn' rid='FN3'>3</xref>
- Author
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Zoltán A. Tökés, Patricia A. Ganz, and William E. Shell
- Subjects
Oncology ,chemistry.chemical_classification ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Renal function ,Cancer ,Radioimmunoassay ,medicine.disease ,Lymphoma ,chemistry ,Internal medicine ,medicine ,Tumor-associated glycoprotein 72 ,Lung cancer ,Glycoprotein ,business - Abstract
A new radioimmunoassay for alpha 1-acid glycoprotein (AGP) for monitoring the therapy of cancer patients was evaluated. Plasma levels of this glycoprotein were measured in 49 normal healthy volunteers, 71 patients with illnesses other than cancer, 190 patients with solid tumors, and 58 patients with hematologic neoplasms. Plasma levels of AGP were elevated in 89% of the solid tumor patients and 87% of the patients with hematologic neoplasms who had newly diagnosed, locally recurrent, or metastatic cancer. Only 18% of patients with illnesses other than cancer and normal renal function had elevations of plasma AGP. Serial measurements of AGP may be useful for monitoring therapy in several tumor types, including small-cell lung cancer, colon cancer, lymphoma, and non-small-cell lung cancer.
- Published
- 1983
- Full Text
- View/download PDF
26. Immunohistochemical localization of keratin in human prostate
- Author
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Kiyoaki Kitajima and Zoltán A. Tökés
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Cytoplasm ,Urology ,Population ,Prostatic Hyperplasia ,Biology ,Adenocarcinoma ,Immunoenzyme Techniques ,Keratin ,medicine ,Humans ,education ,Keratin pearl ,chemistry.chemical_classification ,education.field_of_study ,integumentary system ,Histocytochemistry ,Prostate ,Prostatic Neoplasms ,Hyperplasia ,medicine.disease ,Oncology ,chemistry ,Cancer cell ,Keratin 7 ,Keratin 8 ,Keratins - Abstract
The localization of keratin was investigated in normal human prostate, benign prostatic hyperplasia (BPH), and prostatic adenocarcinoma using immunohistochemical technique on frozen tissue sections. The purpose of this study was to identify changes in the distribution patterns of keratin due to malignancy. In normal and benign tissue specimens, keratin was detected in the cytoplasm of basal cells and glandular epithelial cells. In the glandular epithelial cells keratin was found as a deposit of fine granules. In the basal cells, the positive staining for keratin had a uniform distribution in the scanty cytoplasm. In specimens of prostatic adenocarcinoma, the basal cells retained a strong positive reaction for keratin. The shapes and the distributions of basal cells were markedly different in malignant specimens. Basal cells formed a discontinuous layer and surrounded the population of neoplastic cells in tissue sections containing the cribriform patterns. The cells expressed characteristic protrusions into extracellular spaces between the cancer cells. Keratin-positive granules were demonstrated in the adenocarcinoma cells as well. These granules had slightly smaller sizes and were distributed randomly. The study demonstrates that the immunohistochemical localization of keratin provides a refinement for the characterization of cells in tissue sections of prostate.
- Published
- 1986
27. Plasma sialyltransferase in patients with breast cancer
- Author
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Yeu‐Tsu N. Lee, Zoltán A. Tökés, and Csaba Csipke
- Subjects
medicine.medical_specialty ,Pathology ,Sialyltransferase ,Breast Neoplasms ,Disease ,Gastroenterology ,Breast cancer ,Transferases ,Internal medicine ,Medicine ,Humans ,biology ,business.industry ,Albumin ,Soft tissue ,General Medicine ,medicine.disease ,Alkaline Phosphatase ,Sialyltransferases ,Carcinoembryonic Antigen ,Oncology ,Peripheral blood lymphocyte ,biology.protein ,Alkaline phosphatase ,Surgery ,Neoplasm Recurrence, Local ,Breast carcinoma ,business - Abstract
Sialyltransferase enzyme levels (Sialtx) CEA, and 10 standard laboratory tests were studied in 50 patients with treated, recurrent, or disseminated breast carcinoma. All groups of patients had elevated mean Sialtx activity (CPM/mg protein) as compared with normal controls. Sialtx levels (expressed as % of normal controls) of patients with disseminated lesions were significantly elevated as compared to patients without evidence of disease or with only soft tissue recurrences, whereas CEA and alkaline phosphatase levels were significantly elevated (peripheral blood lymphocyte count, total protein and albumin levels significantly decreased) in patients with recurrent disease of all sites. Among patients with disseminated breast cancer and normal CEA levels, about 50% had markedly elevated Sialtx activities. From our limited experience, it appears that Sialtx study is of value when CEA failed to indicate the presence of breast malignancy. Further testing including serial studies should be done to better define its clinical usefulness.
- Published
- 1980
28. Novel mode of cytotoxicity obtained by coupling inactive anthracycline to a polymer
- Author
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Kathryn E. Rogers and Zoltán A. Tökés
- Subjects
Pharmacology ,Antibiotics, Antineoplastic ,Anthracycline ,Chemistry ,Polymers ,Cell ,Daunorubicin ,Biochemistry ,In vitro ,Microspheres ,Coupling (electronics) ,medicine.anatomical_structure ,Mechanism of action ,Covalent bond ,Cell culture ,Glutaral ,medicine ,Animals ,medicine.symptom ,Cytotoxicity ,Idarubicin ,Leukemia L1210 - Abstract
The inactive anthracycline analog 4-demethoxy-7,9-di-epi-daunorubicin was covalently coupled to polyglutaraldehyde microspheres. The polymer-bound analog acquired significant cytostatic activity as evaluated with doxorubicin resistant and sensitive murine L1210 leukemia cells. A suggested multiple membrane interaction at the cell surface may represent a novel mechanism of cytotoxicity.
- Published
- 1984
29. Digestive enzymes secreted by the carnivorous plant Nepenthes macferlanei L
- Author
-
Susan M. Chambers, Wang Chee Woon, and Zoltán A. Tökés
- Subjects
chemistry.chemical_classification ,Carnivorous plant ,Nepenthesin ,Proteases ,biology ,Plant Science ,Enzyme ,Pepsin ,Biochemistry ,chemistry ,Digestive enzyme ,Genetics ,biology.protein ,Amylase ,Lipase - Abstract
At least two proteases are present in the secretion of the pitchers of Nepenthes macferlanei, a major one with an estimated molecular weight of 59000 and a minor one of 21000. The specificity of the major enzyme, nepenthesin, was broader than previously reported, and strikingly similar to that of pepsin. Lipase activity was also demonstrated, while no amylase activity was present.
- Published
- 1974
30. The synthesis of a proteinase inhibitor, alpha-1-antichymotrypsin, by human breast epithelial cells
- Author
-
Sandra J. Gendler, Gerald B. Dermer, and Zoltán A. Tökés
- Subjects
alpha 1-Antichymotrypsin ,Cell ,Breast Neoplasms ,Cathepsin G ,Adenocarcinoma ,Organ culture ,Biochemistry ,Alpha 1-antichymotrypsin ,Epithelium ,Cell Line ,chemistry.chemical_compound ,Organ Culture Techniques ,medicine ,Chymotrypsin ,Humans ,Protease Inhibitors ,Breast ,skin and connective tissue diseases ,Gel electrophoresis ,chemistry.chemical_classification ,biology ,General Medicine ,Molecular biology ,Molecular Weight ,medicine.anatomical_structure ,chemistry ,Cell culture ,Immunology ,biology.protein ,Female ,Antibody ,Glycoprotein - Abstract
The synthesis and release of glycoproteins were studied in organ cultures of human breast surgical specimens and in established breast epithelial cell lines, MCF-7 and MDA-MB-231. Biosynthesis was monitored by the incorporation of 14C-glucosamine. Labeled macromolecules in the culture supernatants were analyzed by biochemical and immunological techniques. One to 8% of the labeled glycoproteins from benign breast and infiltrating ductal carcinoma specimens was precipitated by antibodies produced against human serum alpha-1-antichymotrypsin. Twelve percent of the total glycoproteins from the culture supernatants of the MCF-7 cell line was identified as alpha-1-antichymotrypsin. Both the normal serum and the human breast epithelia-derived proteinase inhibitor can be resolved into similar subclasses by two-dimensional gel electrophoresis. MDA-MD-231 and MCF-7 cells which were extensively washed with EDTA, serum-free medium, and phosphate-buffered saline retain this proteinase inhibitor on their cell surfaces. Three to 4% of the total cell-surface iodinated components was immunoprecipitated by these specific antibodies. Since alpha-1-antichymotrypsin is a potent inhibitor of neutral proteinases such as cathepsin G, the demonstration of its synthesis by benign and malignant breast epithelial cells is of considerable interest. This glycoprotein may represent the epithelia's own protective shield of cell surface components and the cell's attempt to moderate the effects of invading leukocytes. In addition, it may play a regulatory role in the maintenance of three-dimensional glandular structures.
- Published
- 1981
31. ChemInform Abstract: Synthesis, Biological Evaluation, and Quantitative Structure-Activity Relationship Analysis of 2-Hydroxy-1H-isoindolediones as New Cytostatic Agents
- Author
-
Eric J. Lien, Carcy L. Chan, and Zoltán A. Tökés
- Subjects
Quantitative structure–activity relationship ,chemistry.chemical_compound ,Chemistry ,Stereochemistry ,Cytostatic agents ,Substituent ,Ic50 values ,General Medicine ,Inhibitory postsynaptic potential ,Inhibitory effect ,Lower activity ,Biological evaluation - Abstract
A series of 16 derivatives of 2-hydroxy-1H-isoindole-1,3-diones was designed and synthesized as potential antitumor agents. The cytostatic activity against L1210 cell growth of these compounds was studied, and their IC50 values were found to be in the range of 10(-4) to 10(-8) M. Quantitative structure-activity relationship analysis of these compounds showed that the inhibitory effect was well correlated with the electronic and the lipophilic parameters. Derivatives having a substituent with strongly electron-donating properties at the 6-position showed enhanced inhibitory activity while compounds having an electron-withdrawing group at the same position showed lower activity.
- Published
- 1987
- Full Text
- View/download PDF
32. Preparation of neuramin-lactose from bovine colostrum
- Author
-
Zoltán A. Tökés and Lewis W. Mayron
- Subjects
Clostridium ,Chromatography ,Sodium ,Colostrum ,Evaporation ,chemistry.chemical_element ,Lactose ,General Medicine ,chemistry.chemical_compound ,Hydrolysis ,chemistry ,Pregnancy ,Galactose ,Sialic Acids ,Animals ,Cattle ,Female ,Neuraminic Acids - Published
- 1960
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