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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
    Chromatographic purification steps involved in the synthesis of prodrug-liposome-antibody-complexes (1988)
    Springer
    Chromatographia 25 (1988), S. 210-214 
    Details
    ISSN: 1612-1112
    Keywords: Liposomes ; Biotin-avidin-coupling ; Biotinylated antibody ; Drug targeting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The cytostatic effect of the widely used antitumor drug 1-β-D-arabinofuranosyl cytosine (ara C) can be improved by its chemical derivatization to lipophilic prodrugs. We have incorporated these prodrugs together with lipophilic biotin derivatives into membranes of unilamellar liposomes. Monoclonal antibodies were coupled to the biotin residues of the liposomes via avidin-biotin complexation resulting in prodrug-liposome-antibody complexes whichin vitro preferably bind to cells selectively recognized by the immobilized antibodies. The results open a promising way of drug targeting. The components and liposomal derivatives used for the stepwise preparation of the prodrug-liposome antibody complex are purified by means of preparative liquid chromatography. Lipophilic membrane components are chromatographed on silica gel, antibodies on hydroxylapatite and liposomal derivatives on Ultrogel AcA 22 columns. Concentration and desalting are achieved by ultrafiltration. The purification process can be quantitatively pursued by labelling with radioactive components.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02316446
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  • 6
    Electronic Resource
    Electronic Resource
    Synthesis and In Vitro Antitumor Activity of 2′-Deoxy-5-fluorouridylyl-(3′→5′)-2′-deoxy-5-fluoro-N4-octadecylcytidine: A New Amphiphilic Dinucleoside Phosphate (1997)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1997 (1997), S. 413-417 
    Details
    ISSN: 0947-3440
    Keywords: 2′-Deoxy-5-fluorouridine derivatives ; Phosphotriester method ; Liposomes ; Antitumor agents ; MIA PaCa 2 pancreas tumor cell line ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The new amphiphilic dinucleoside phosphate, 2′-deoxy-5-fluorouridylyl-(3′→5′)-2′-deoxy-5-fluoro-N4-octadecylcytidine (4) was synthesized on a gram scale, using the phosphotriester method, starting from the cytostatic drug 2′-deoxy-5-fluorouridine (5FdU) and 2′-deoxy-5-fluoro-N4-octadecylcytidine (1d). In in vitro clonogenic growth assays using the human pancreatic adenocarcinoma cell line MIA PaCa 2, the amphiphilic dimer was significantly more effective than the parent monomeric 5FdU. The IC50 of the dimer was 10 μg/ml when applied as an aqueous solution and 12 μg/ml when given as a liposome dispersion, whereas with 5FdU the IC50 concentration was not reached within the concentration range used.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.199719970220
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  • 7
    Electronic Resource
    Electronic Resource
    Synthese und Eigenschaften von N4-Hexadecyl-2′-desoxycytidylyl-(3′-5′)-5-ethyl-2′-desoxyuridin und 2′-Desoxythymidylyl-(3′-5′)-N4-hexadecyl-1-β-D-arabinofuranosylcytosin, zwei Vertreter einer neuen Prodrug-Gruppe (1994)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1994 (1994), S. 277-282 
    Details
    ISSN: 0170-2041
    Keywords: Prodrugs ; Cytidine derivatives ; Cytosine derivatives ; Thymidine derivatives ; Amphiphilic dinucleoside phosphates ; Hydrogen phosphonate method ; Liposomes ; Nucleosides ; Nucleotides ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Synthesis and Properties of N4-Hexadecyl-2′-deoxycytidylyl-(3′-5′)-5-ethyl-2′-deoxyuridine and 2′-Deoxythymidylyl-(3′-5′)-N4-hexadecyl-1-β-D-arabinofuranosylcytosine, Two Representatives of a New Kind of ProdrugsThe gram-scale condensation of N4-hexadecyl-2′-deoxycytidine with the antiviral 5-ethyl-2′-deoxyuridine and of 2′-deoxythymidine with the antineoplastic N4-hexadecyl-1-β-D-arabinofuranosylcytosine via a 3′-5′-phosphodiester linkage using the hydrogen phosphonate method is described. The purity and the structure of the synthetic products were determined chromatographically (TLC, HPLC) and spectroscopically (MS-MS, 2D-NMR). The resulting amphiphilic dinucleoside phosphates represent two examples of a new kind of prodrugs in which lipophilic or hydrophilic nucleoside residues are applied for the masking of 5′-phosphorylated nucleoside analogues which are known as chemotherapeutics. The prodrugs are soluble in water and can also be incorporated together with matrix lipids into stable liposome dispersions.
    Additional Material: 4 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.199419940309
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