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  • 1
    Electronic Resource
    Electronic Resource
    Comparative cytotoxicity and pharmacokinetics of antimelanoma immunotoxins containing either natural or recombinant gelonin (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 343-348 
    Details
    ISSN: 1432-0843
    Keywords: Key words Immunotoxins ; Gelonin ; Melanoma ; Recombinant toxins ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Immunotoxins are a class of targeted therapeutic agents under development by various research groups. The murine monoclonal antibody designated ZME-018 recognizes a high molecular weight glycoprotein present on most human melanoma cells and biopsy specimens and has been utilized for clinical imaging studies in patients with melanoma. The plant toxin gelonin is a ribosome-inactivating protein (RIP) with n-glycosidase activity similar to that of ricin A chain. In previous studies by our group, the gelonin toxin was sequenced, cloned and expressed in E. coli. The purified recombinant gelonin (RG) was found to have identical protein synthesis inhibitory activity to that of natural gelonin (NG). For comparative purposes, chemical conjugates of antibody ZME and either RG or NG were produced using the heterobifunctional crosslinking reagents SPDP and SMPT. The ZME-NG and ZME-RG immunotoxins were found to be 104- to 105-fold more cytotoxic to antigen-positive human melanoma cells than free toxin. NG toxin alone was cytotoxic to intact cells (IC50 = 100 nM) while RG was nontoxic to cells at doses up to 1 μM. Both ZME-NG and ZME-RG immunoconjugates were nontoxic to antigen-negative (Me-180) cells. ZME-RG immunotoxins constructed with the more stable SMPT reagent were slightly more effective in culture than conjugates made with SPDP. Tissue distribution studies in tumor-bearing nude mice demonstrated that tumor uptake of the ZME-RG immunotoxin was similar to that of the intact ZME antibody with reduced distribution to normal organs compared to an immunoconjugate produced with NG. Pharmacokinetic studies showed that the terminal-phase plasma half-life of ZME-RG was similar to that of ZME itself (42 h vs 50 h) and almost threefold higher than that of ZME-NG (11.5 h). The area under the concentration curve (Cxt) for ZME-RG was 50% lower than that for ZME due to an increased apparent volume of distribution (Vda) but was almost tenfold higher than the Cxt for ZME-NG. These studies suggest that immunoconjugates comprising RG demonstrate identical in vitro cytotoxic effects to immunoconjugates produced with NG and immunotoxins with RG display improved in vivo pharmacodynamics and tissue distribution compared to immunotoxins containing NG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050987
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  • 2
    Electronic Resource
    Electronic Resource
    Scaling behaviour of heartbeat intervals obtained by wavelet-based time-series analysis (1996)
    [s.l.] : Nature Publishing Group
    Nature 383 (1996), S. 323-327 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] A random process is stationary if its statistical characteristics are invariant under time shifts, that is, if they remain the same when t is replaced byt + A, where A is arbitrary. The probability densities, together with the moment and correlation functions, do not then depend on the absolute ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/383323a0
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  • 3
    Electronic Resource
    Electronic Resource
    Multifractality in human heartbeat dynamics (1999)
    [s.l.] : Macmillan Magazines Ltd.
    Nature 399 (1999), S. 461-465 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] There is evidence that physiological signals under healthy conditions may have a fractal temporal structure. Here we investigate the possibility that time series generated by certain physiological control systems may be members of a special class of complex processes, termed multifractal, which ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/20924
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  • 4
    Electronic Resource
    Electronic Resource
    Heartbeat synchronized with ventilation (1998)
    [s.l.] : Macmillan Magazines Ltd.
    Nature 392 (1998), S. 239-240 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] It is widely accepted that cardiac and respiratory rhythms in humans are unsynchronised. However, a newly developed data analysis technique allows any interaction that does occur in even weakly coupled complex systems to be observed. Using this technique, we found long periods of hidden ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/32567
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin (1995)
    Springer
    Cancer immunology immunotherapy 40 (1995), S. 339-345 
    Details
    ISSN: 1432-0851
    Keywords: Monoclonal antibodies ; Immunotoxin ; Immunotherapy ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study describes the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of125I-labeled ZME-018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half-life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h). The initial volume of distribution of the ZME-gelonin was also higher compared to that of ZME alone (2.85 ml compared to 1.91 ml) suggesting an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME-gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 μCi·ml−1 x min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of125I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9±0.5 and 1.5±0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm3) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, a 213% increase in mean survival time compared with the saline treatment (14.2±2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01519635
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    Paper (German National Licenses)
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics, tissue distribution, and in vivo antitumor effects of the antimelanoma immunotoxin ZME-gelonin (1995)
    Springer
    Cancer immunology immunotherapy 40 (1995), S. 339-345 
    Details
    ISSN: 1432-0851
    Keywords: Key words: Monoclonal antibodies ; Immunotoxin ; Immunotherapy ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Antibody ZME-018 is directed against the gp240 glycoprotein on the surface of more than 80% of human melanoma cell lines and fresh biopsy specimens. Previous studies in our laboratory described the in vitro cytotoxicity and specificity of an immunoconjugate composed of mAb ZME-018 and the plant toxin gelonin. The present study describes the in vivo pharmacokinetics and therapeutic effects of ZME-gelonin in human xenograft/nude mouse models. Pharmacokinetic studies of 125I-labeled ZME-018 and ZME-gelonin demonstrated a shorter terminal-phase plasma half-life of the immunoconjugate than native ZME (20.6 h compared to 41.3 h). The initial volume of distribution of the ZME-gelonin was also higher compared to that of ZME alone (2.85 ml compared to 1.91 ml) suggesting an enhanced distribution of the conjugate outside the vasculature. The corresponding area under the concentration/time curve for the ZME-gelonin conjugate was 40% lower than that of ZME alone (80.8 compared to 139.6 μCi ⋅ ml-1×min). In nude mice bearing well-developed human tumor A375 melanoma xenografts, administration of 125I-labeled ZME and ZME-gelonin resulted in tumor-to-blood ratios of 1.9±0.5 and 1.5±0.6 respectively by 72 h. Compared with ZME, ZME-gelonin conjugate caused an increase in the content of radiolabel in kidney, spleen and liver. Treatment of nude mice bearing well-developed (150 mm3) s.c. A375-M xenografts with divided doses of ZME-gelonin, ZME, gelonin, or saline resulted in suppression of tumor growth in the immunotoxin group but virtually no retardation of tumor growth in the control groups. Using a murine model for a rapidly growing lethal metastatic human melanoma, treatment with ZME-gelonin resulted in a mean survival of 44 days, a 213% increase in mean survival time compared with the saline treatment (14.2±2 day survival). Given these encouraging results, we are proceeding with further preclinical development of this immunotoxin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01519635
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    Paper (German National Licenses)
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  • 7
    Electronic Resource
    Electronic Resource
    An antimelanoma immunotoxin containing recombinant human tumor necrosis factor: tissue disposition, pharmacokinetic, and therapeutic studies in xenograft models (1995)
    Springer
    Cancer immunology immunotherapy 40 (1995), S. 322-328 
    Details
    ISSN: 1432-0851
    Keywords: TNF ; Immunotoxins ; Melanoma ; Pharmacokinetics ; Xenograft models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of monoclonal antibody conjugates to re-direct plant or bacterial toxins, chemotherapeutic agents and radionuclides to selected target cells has been well-documented. Recombinant human tumor necrosis factor (TNF) is a macrophage-derived, non-glycosylated (17 kDa) peptide with a broad range of biological and immunological effects including antiviral activity, cytotoxic and cytostatic effects. A conjugate of the antimelanoma antibody ZME-018 and TNF in previous studies has shown melanoma-selective cytotoxic effects in vitro. Pharmacokinetic studies of the ZME-TNF immunotoxin showed that the agent cleared from plasma biphasically with α-and β-phase half-lives similar to that of ZME itself (72 min and 36 h compared to 84 min and 41 h respectively). In contrast, TNF itself was cleared rapidly from plasma with a terminalphase half-life of only 2.7 h. The clearance rate of ZME-TNF from plasma (Clp) was almost tenfold more rapid than for ZME (1.1 versus 0.16 ml/kg x min) but was threefold slower than the clearance for TNF itself (3.4 ml/kg x min). Tissue distribution studies in nude mice bearing human melanoma xenografts showed similar tumor localization of the immunotoxin compared to the free antibody and slightly higher concentrations in liver and kidney compared to ZME itself. Treatment of nude mice bearing well-developed A375 tumors with the immunotoxin resulted in a statistically significant (P〈0.002) suppression in tumor growth rate (fivefold increase) compared to saline-treated controls, which increased 20-fold over the same period. These studies demonstrate the feasibility of this approach and suggest that TNF may represent a non-antigenic alternative to immunotoxins containing plant and bacterial toxins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01519633
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    Paper (German National Licenses)
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