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  • 1
    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
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 2
    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
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Early events in the antiproliferative action of tumor necrosis factor are similar to the early events in epidermal growth factor growth stimulation (1989)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 41 (1989), S. 139-157 
    Details
    ISSN: 0730-2312
    Keywords: epidermal growth factor receptor ; tyrosine kinase activity ; phosphorylation ; c-myc ; control of cell growth ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The process of TNF-induced cytotoxicity is complex but appears to be mediated through a TNF-specific cell surface receptor. Recent evidence suggests that TNF action on tumor cells may be antagonized by epidermal growth factor (EGF) and other EGF-receptor modulatory peptides implicating a role for EGF-R in the process of TNF-induced cytotoxicity. In the present report, we investigated the biochemical actions of TNF of several biochemical events known to occur in the process of EGF signal transduction in intact cells. The actions of TNF were compared directly to those of EGF in both TNF-sensitive and -resistant tumor cell lines.In TNF-sensitive ME-180 cervical carcinoma cells, TNF (20 ng/ml) stimulated the tyrosine protein kinase activity of the EGF-receptor (EGF-R) fivefold when measured by receptor autophosphorylation in an immune complex kinase assay. TNF activation of EGF-R kinase activity in ME-180 was measurable 10 min after TNF incubation and enzymatic activity remained elevated 20 min after TNF addition. Activition of the receptor by TNF correlated with increased 32P incorporation into EGF-R protien when receptor was immunoprecipitated from 32P-equilibrated cells following a 20 min incubation with TNF. Acid hydrolysis of EGF-R protein isolated from TNF-treated ME-180 cells demonstrates an increase in the phosphotyrosine content of EGF-R when compared to receptor isolated from untreated cells. The results suggest that TNF increased EGF-R tyrosine protein kinase activity and the state of EGF-receptor tryosine phosphorylation in a manner similar to that reported for EGF. However, TNF does not appear to be structurally related to EGF since TNF was unable to directly activate EGF-R when incubated with extensively washed immunoprecipitates of EGF-R.In TNF-resistant T24 bladder carcinoma cells, TNF failed to alter EGF-R tyrosine protein kinase activity although both EGF and phorbol ester were shown to modulate the enzymatic activity of the receptor in these cells. These results indicate that the ability of TNF to modulate EGF-R kinase in target cells may correlate with its cytotoxic actions on TNF-sensitive tumor cells.Other biochemical activities associated with the induction or regluation of cellular growth were examined in TNF- or EGF-treated tumor cells. EGF stimulated a rapid 8-16-fold increase in the expression of the proto-oncogene c-myc when analyzed by dot-blot analysis of total cellular RNA or Northern blot hybridization of polyadenylated RNA. TNF treatment failed to alter c-myc expression in ME-180 cells when analyzed by either technique. The two structurally distinct peptides, TNF and EGF, induced similar patterns of ornithine decarboxylase activity (the rate-limiting enzyme in polyamine biosynthesis) in ME-180 cells but differed in their relative magnitude of maximal induction. Similar results were obtained in TNF- or EFG-treated T24 cells, suggesting the effects of TNF on polyamine biosynthesis are not related to its cytotoxic mechanism of action. These results indicate that TNF shares some of the early biochemical actions of EGF in tumor cells and some of these effects may be related to the mechanism of TNF-induced cytotoxicity.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240410305
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Tumor necrosis factor stimulates ornithine decarboxylase activity in human fibroblasts and tumor target cells (1991)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 46 (1991), S. 69-77 
    Details
    ISSN: 0730-2312
    Keywords: cytokines ; cell proliferation ; polyamines ; cytotoxicity ; growth factors ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The activity of the polyamine biosynthetic enzyme, ornithine decarboxylase (ODC), has been shown to be rapidly modulated by a variety of growth regulatory molecules. In this report the effect of the growth modulatory peptide, tumor necrosis factor, on ODC activity was examined on two cell lines which express equivalent TNF binding properties, but differ in their growth response when exposed to this factor. TNF treatment of WI-38 fibroblasts stimulated both their growth and induced ODC activity 5-10-fold when measured 6-24 h after TNF incubation. TNF induced cytotoxicity in ME-180 cervical carcinoma cells and, interestingly, stimulated both ODC activity (3-6-fold) and putrescine accumulation when measured prior to the onset of cytotoxicity. Induction of ODC was TNF concentration-dependent and paralleled the concentration-dependency for cytotoxicity. Based upon studies with cycloheximide, de novo protein biosynthesis was required for TNF-mediated ODC induction in ME-180 cells.The effects of other growth inhibitory peptides and growth factors were analyzed for their combined effect on ODC activity in TNF-treated or untreated ME-180 cells. Interferon gamma treatment had no significant effect on basal ODC activity but inhibited TNF-mediated ODC induction by ∼50%. EGF treatment resulted in a potent stimulation of ODC activity which was not effected by TNF pre-treatment or coadministration on ME-180 cells. These results suggest that TNF has properties which are similar to those of a growth factor and distinct from those of other growth inhibitory peptides. The early growth factor-like actions of TNF occur on both normal fibroblasts and some tumor cells and evidence suggests that these effects are antagonistic to the antiproliferative effects of TNF.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240460111
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    Paper (German National Licenses)
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