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  • 1
    Electronic Resource
    Electronic Resource
    Cellular pharmacology ofN 4-hexadecyl-1-β-D-arabinofuranosylcytosine in the human leukemic cell lines K-562 and U-937 (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 483-492 
    Details
    ISSN: 1432-0843
    Keywords: N 4-Hexadecyl-1-β-d-arabinofuranosylcytosine, NHAC ; Cellular pharmacology ; Liposomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The mechanisms of cytotoxicity, cellular drug uptake, intracellular drug distribution, cellular pharmacokinetics, formation of arabinofuranosylcytosine triphosphate (ara-CTP), and DNA incorporation ofN 4-hexadecyl-1-β-d-arabinofuranosylcytosine (NHAC), a new lipophilic derivative of arabinofuranosylcytosine (ara-C) formulated in small unilamellar liposomes, were determined in vitro in the human leukemic cell lines K-562 and U-937. Furthermore, the induction of erythroid differentiation by NHAC was tested in K-562 cells. The cytotoxicity of NHAC in both cell lines was not influenced by the deoxycytidine (dCyd) concentration or the presence of the nucleoside-transport-blocking agent dipyridamole as demonstrated in coincubations with dCyd and/or dipyridamole, where-as in contrast, the cytotoxicity of ara-C was decreased additively by both drugs. As compared with ara-C, the uptake of NHAC displayed up to 16- and 5-fold increases in K-562 and U-937 cells, respectively, depending on the drug concentration. Studies of the drug distribution and pharmacokinetics of NHAC revealed a depot effect for NHAC in the cell membranes, resulting in half-lives 2.6 and 1.4 times longer than those of ara-C in the two cell lines. The ara-CTP concentrations derived from NHAC were 150- and 75-fold lower at a drug concentration of 1 μM in K-562 and U-937 cells, respectively. The DNA incorporation of the drugs observed after incubation with 2 μM NHAC was 60- and 30-fold lower as compared with that seen at 2 μM ara-C in the two cell lines. Furthermore, NHAC was capable of inducing irreversible erythroid differentiation to a maximum of only 22% of K-562 cells, where-as ara-C induced differentiation at a drug concentration 100-fold lower in 50% of the cells. These results indicate a mechanism of cytotoxicity for NHAC that is independent of the nucleoside transport mechanism and the phosphorylation pathway and suggest that the mechanisms of action of NHAC are significantly different from those of ara-C. Therefore, NHAC might be used for the treatment of ara-C-resistant malignancies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685798
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  • 2
    Electronic Resource
    Electronic Resource
    Cellular pharmacology of N4-hexadecyl-1-β-D-arabinofuranosylcytosine in the human leukemic cell lines K-562 and U-937 (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 483-492 
    Details
    ISSN: 1432-0843
    Keywords: Key words N4-Hexadecyl-1-β-D-arabinofuranosylcytosine ; NHAC ; Cellular pharmacology ; Liposomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The mechanisms of cytotoxicity, cellular drug uptake, intracellular drug distribution, cellular pharmacokinetics, formation of arabinofuranosylcytosine triphosphate (ara-CTP), and DNA incorporation of U001N 4-hexadecyl-1-β-D-arabinofuranosylcytosine (NHAC), a new lipophilic derivative of arabinofuranosylcytosine (ara-C) formulated in small unilamellar liposomes, were determined in vitro in the human leukemic cell lines K-562 and U-937. Furthermore, the induction of erythroid differentiation by NHAC was tested in K-562 cells. The cytotoxicity of NHAC in both cell lines was not influenced by the deoxycytidine (dCyd) concentration or the presence of the nucleoside-transport-blocking agent dipyridamole as demonstrated in coincubations with dCyd and/or dipyridamole, whereas in contrast, the cytotoxicity of ara-C was decreased additively by both drugs. As compared with ara-C, the uptake of NHAC displayed up to 16- and 5-fold increases in K-562 and U-937 cells, respectively, depending on the drug concentration. Studies of the drug distribution and pharmacokinetics of NHAC revealed a depot effect for NHAC in the cell membranes, resulting in half-lives 2.6 and 1.4 times longer than those of ara-C in the two cell lines. The ara-CTP concentrations derived from NHAC were 150- and 75-fold lower at a drug concentration of 1 μM in K-562 and U-937 cells, respectively. The DNA incorporation of the drugs observed after incubation with 2 μM NHAC was 60- and 30-fold lower as compared with that seen at 2 μM ara-C in the two cell lines. Furthermore, NHAC was capable of inducing irreversible erythroid differentiation to a maximum of only 22% of K-562 cells, whereas ara-C induced differentiation at a drug concentration 100-fold lower in 50% of the cells. These results indicate a mechanism of cytotoxicity for NHAC that is independent of the nucleoside transport mechanism and the phosphorylation pathway and suggest that the mechanisms of action of NHAC are significantly different from those of ara-C. Therefore, NHAC might be used for the treatment of ara-C-resistant malignancies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685798
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  • 3
    Electronic Resource
    Electronic Resource
    Oral antitumour activity in murine L1210 leukaemia and pharmacological properties of liposome formulations ofN 4-alkyl derivatives of 1-β-d-arabinofuranosylcytosine (1996)
    Springer
    Journal of cancer research and clinical oncology 122 (1996), S. 102-108 
    Details
    ISSN: 1432-1335
    Keywords: Lipophilic AraC derivatives ; Oral activity ; Toxicity ; Pharmacokinetics ; Liposomes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The oral cytostatic activity in L1210 mouse leukaemia of the two newN 4-alkyl derivatives of 1-β-d-arabinofuranosylcytosine (AraC),N 4-hexadecyl- andN 4-octadecyl-1-β-d-arabinofuranosylcytosine (NH- AraC, NO-AraC) was investigated. In contrast to AraC, both derivatives were highly cytostatic after oral application as liposome formulations. With treatment schedules of five consecutive dosages or with two applications on days 1 and 4 after intravenous tumour cell inoculation with a total dose of 470–1000 mg/kg NH- AraC or NO-AraC, 70%–100% of the treated animals were cured. The lethal dose in healthy ICR mice after a single intraperitoneal application, corresponding to the LD50, was 524 mg/kg for NO-AraC, whereas NH- AraC proved to be less toxic. The haematological toxicity. remained moderate for both drugs with a mild leucopenia and a drop in platelet counts, which recovered 4–6 days after treatment. The erythrocytes were not affected and haemolytic toxicities were absent. As non-haematological toxicities, at high drug concentrations, a pronounced atrophy of the rapidly dividing epithelia of the small intestines and of the white pulp of the spleen were observed. The blood levels of NH-AraC given orally reached values comparable to those after parenteral application of a four-times lower dose of NH-AraC, suggesting a moderate bioavailability. Thus, these two lipophilic derivatives of AraC are compounds with a potential for the oral treatment of malignant diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01226267
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  • 4
    Electronic Resource
    Electronic Resource
    Lipophilic 1-β-d-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model (1996)
    Springer
    Journal of cancer research and clinical oncology 122 (1996), S. 723-726 
    Details
    ISSN: 1432-1335
    Keywords: Lipophilic cytosine arabinoside derivatives ; Liposomes ; Oral therapy ; L1210 leukemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract TheN 4-alkylcytosine arabinoside derivativeN 4-octadecyl-AraC (AraC-Ocd, NOAC) and the (1-octadecylglycero-3-phospho)-AraC (Ocd-GroP-AraC, OPA) conjugate are new lipophilic derivatives of the cytostatic drug 1-β-d-arabinofuranosylcytosine (AraC) that produce high antileukemic effects in the L1210 murine leukemia model when administered orally or parenterally as liposomal formulations. Between 83% and 100% of the treated animals were cured after five consecutive daily oral drug applications with a total dose of 1 mmol/kg AraC-Ocd or Ocd-GroP-AraC. Corresponding results were obtained after parenteral therapy on days 2 and 6 after tumor inoculation with five- to ten-fold lower concentrations of these two compounds. A comparable cytotoxic activity was found with the orally active AraC-5′-(n-stearyl phosphate). However, because of its strong hemolytic toxicity this derivative cannot be used for parenteral therapy. Another AraC conjugate, which was modified with two long-chain hydrocarbons, the (1-octadecylglycero-3-phospho)-N 4-hexadecyl-AraC was, probably because of poor oral bioavailability, only active when applied parenterally. The new lipophilic AraC derivatives AraC-Ocd and Ocd-GroP-AraC are compounds with a high potential for the oral treatment of leukemias and possibly also of solid tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01209119
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  • 5
    Electronic Resource
    Electronic Resource
    Synthese von tryptophanpeptid-gelen auf polyacrylbasis zur untersuchung der peptid-nukleotid-wechselwirkung (1976)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 177 (1976), S. 645-652 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Description / Table of Contents: The synthesis of ω-(N-acryloyl)tryptophanpeptide monomers (8) and tryptophanpeptide gels obtained by radical copolymerisation of the monomers 8 with diacrylates is described. Peptide-nucleotide interactions were studied by column chromatography employing a tryptophanpeptide gel containing five tryptophyl residues as the stationary phase. Deoxyribonucleotides are retarded only to a small extent, deoxyribonucleosides to a somewhat higher extent; adenosine is strongly retarded and well separated. These results demonstrate, that gels of peptides based on a polyacrylic matrix are suitable for the investigation of peptide-nucleotide interactions and for affinity-chromatography. Furthermore, these gels can also be used as specific sorbents for separations of nucleic acid residues on a preparative scale.
    Notes: Die Synthese von ω-(N-Acryloyl)-tryptophanpeptid-Monomeren (8) und deren radikalische Copolymerisation mit Diacrylaten zu Tryptophanpeptid-Gelen wird beschrieben. An einem Tryptophanpeptid-Gel mit fünf Tryptophyl-Resten wird die Peptid-Nukleotid-Wechselwirkung säulenchromatographisch untersucht. Hierbei werden Desoxyribonukleotide nur gering, Desoxyribonukleoside dagegen stärker retardiert. Deutlich von allen Verbindungen abgetrennt ist Adenosin. Aus den Trennergebnissen folgt, daß Peptidgele auf Polyacrylbasis zur Untersuchung der Peptid-Nukleotid-Wechselwirkung und Affinitätschromatographie geeignet sind. Darüber hinaus können diese Gele als spezifische Sorbentien zur Trennung von Nukleinsäurebausteinen auch in präparativem Maßstab verwendet werden.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1976.021770305
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  • 6
    Electronic Resource
    Electronic Resource
    Immobilisierung von polymergebundenen oligodesoxyribocytidylsäuren an DEAE-celluloseFür die Nomenklatur der Nucleinsäurefragmente werden die Regeln der IUPAC Eur. J. Biochem. 15, 203 (1970) verwendet. TPS steht als Abkürzung für 2,4,6-Triisopropylbenzolsulfonsärechlorid, PVAL für Polyvinylalkohol, TEAB für Triethylammonium-hydrogencarbonatpuffer, DEAE-Cellulose für Diethylaminoethyl-Cellulose, QAE-Sephadex für Diethyl-(2-hydroxypropyl)-aminoethyl-cellulose, Tris für α,α,α-Tris(hydroxymethyl)-methylamin, HMPT für Hexamethylphosphorsäuretriamid. 1A260-Einheit ist die Menge bei 260 nm absorbierenden Materials, die, gelöst in 1 ml, eine Absorption von 1 hat. (1981)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 182 (1981), S. 119-131 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: N-Anisoyl-deoxyribocytidine-5′-phosphate is chemically polycondensed. From the polycondensate, oligomers containing four or more monomeric units are isolated chromatographically and subsequently linked to a soluble polyvinylalcohol. After cleavage of the nucleobaseprotecting groups, the unreacted oligodesoxyribocytidylic acids are separated from polyvinylalcohol bound oligomers through ultrafiltration. DEAE-Cellulose is subsequently coated with this polymer-bound oligodeoxyribocytidylic acids. The now obtained PVAL-p(dC)n-DEAE-Cellulose acts as a specific sorbent in template-chromatography.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1981.021820115
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  • 7
    Electronic Resource
    Electronic Resource
    Darstellung von oligothymidinphosphaten durch chemische partialhydrolyse von desoxyribonucleinsäure (1981)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 182 (1981), S. 2015-2030 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The method of preparation of oligo(thymidine phosphate)s by chemical partial hydrolysis of herring sperm DNA is described. The DNA is degraded in three steps to a mixture of oligomeric thymidine phosphates. Homologeous thymidine phosphates of the series p(dT)1-6p; p(dT)1-7, (dT)1-7p; (dT)1-7 are isolated chromatographically from the partial hydrolysate in pure form on a preparative scale. The advantages and disadvantages of this new and simple method in comparison to complicated synthetic procedures are discussed.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1981.021820714
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  • 8
    Electronic Resource
    Electronic Resource
    Preparative synthesis of guanylate-rich fragments of the terminal sequence of macronuclear DNA from hypotrichous ciliates using the phosphotriester method in solutionDedicated to Prof. Dr. E. Bayer on the occasion of his 60th birthday (1987)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 188 (1987), S. 1313-1346 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Guanylate-rich oligodeoxyribonucleotides d(G4T4), d(T4G4), d(T4G4T4), d(G4T4G4), and d(T4G4T4G4) were synthesized in amounts up to 350 mg using the triester method in solution. These oligonucleotides correspond to fragments of the terminal of macronuclear DNA from hypotrichous ciliates. The protected oligonucleotides were obtained by block-condensation of protected 5′-hydroxyl and 3′-phosphate derivatives. Mixtures of 2,4,6-triisopropylbenzenesulfonyl chloride/N-methylimidazole or 2,4,6-trimethylbenzenesulfonyl chloride/N-methylimidazole were used as condensating agents. Different concepts of protecting the nucleotides were investigated and it was found that yields and purities of the resulting oligonucleotides do not depend essentially on the employed concept. The 36mer d(G4T4G4T4G4T4G4T4G4) was obtained by enzymatic phosphorylation of aliquots of the dodecamers d(G4T4G4) and d(T4G4T4), followed by ligation with T4 DNA ligase.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1987.021880609
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  • 9
    Electronic Resource
    Electronic Resource
    Funktionalisierung des perlcopolymerisationsprodukts aus methylacrylat und 1,4-bis(vinyloxy)butan (1986)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 187 (1986), S. 497-512 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The ester groups of copolymer beads, prepared from methyl acrylate and 1,4-bis(vinyloxy)-butane, were substituted by aminolysis with hexamethylenediamine or aminoalcohols. The resulting gel carrying amino groups was transferred into an anion exchanger by alkylation with 2-chloroethanol or into a cation exchanger by reaction with succinic anhydride. Hydrazinolysis of the starting copolymer beads resulted in gels with hydrazide groups which subsequently can be derivatized. Gels with hydroxyl groups linked to the matrix by means of spacers were obtained by reaction of the succinylated gels with 2-aminoethanol. Phosphorylation of these hydroxyl groups afforded strongly acidic cation exchangers. The yields of the derivatized products are higher and the preparations are easier than those of the known methods. The 11 gel derivatives synthesized from the starting gel are mechanically stable, resistent to hydrolysis in the pH range between 1 and 14, chemically stable at temperatures up to 130°C and obtainable with a variety of pore sizes. The derivatized, cross-linked polymer beads, applicable in aqueous systems as well as in organic solvents, should find application in chromatography, in solid-phase synthesis and as basic gels in biotechnical processes.
    Additional Material: 3 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1986.021870303
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  • 10
    Electronic Resource
    Electronic Resource
    Immobilisierung von geschützten nucleosiden und mononucleotiden an funktionalisierte perlcopolymerisationsprodukte aus methylacrylat und 1,4-bis(vinyloxy)butan (1987)
    New York : Wiley-Blackwell
    Die Makromolekulare Chemie 188 (1987), S. 2277-2291 
    Details
    ISSN: 0025-116X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Protected nucleic acid components were coupled to eight differently functionalized bead copolymers, prepared from methyl acrylate and 1,4-bis(vinyloxy)butane, via amid-, urea-, phosphotriester- or carboxylic acid ester linkages. The immobilization was performed by methods used in nucleic acid chemistry. The obtained gels carry 1 to 300 μmol per gram of nucleoside or nucleotide derivatives. The yield of derivatization was found to be first of all determined by steric effects of the gel matrix, the size of the nucleic acid component and the route of synthesis selected. Anchor groups, arranged via long spacers, were not effective for the immobilization of nucleic acid components. A “carboxylate-gel” which can immobilize 300 μmol per gram of a nucleoside derivative may serve as support in the solid phase synthesis of oligonucleotides in large scale.
    Additional Material: 3 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/macp.1987.021881004
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