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  • 1.
    Alexeyev, O A
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Stigbrand, Torgny
    Settergren, Bo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hantavirus antigen detection using human serum immunoglobulin M as the capturing antibody in an enzyme-linked immunosorbent assay.1996In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 54, no 4, p. 367-71Article in journal (Refereed)
    Abstract [en]

    An enzyme-linked immunosorbent assay (ELISA) was developed to detect different hantavirus antigens in cell culture; i.e. Puumala (PUU), Hantaan (HTN), and Dobrava (DOB) viruses. The assay was based on binding human serum immunoglobulin M (IgM) antibodies to the solid phase by use of goat anti-IgM antibodies. The captured IgM antibodies were present in the acute phase serum from two patients: one infected in Sweden and the other in Bosnia. Antigens being bound to the solid phase by the human anti-PUU and anti-DOB/HTN IgM antibodies were detected by a broadly reacting polyclonal rabbit anti PUU-recombinant nucleocapsid protein antiserum. The IgM isotype was proven to be at least five times more efficient than IgG when used as the capturing antibody. The sensitivity of the PUU antigen ELISA was approximately 0.5 ng/ml, as measured by titration with a PUU recombinant nucleoprotein antigen. Cell-associated PUU antigen in tissue culture was seen after 48 hr by the PUU-ELISA and after 96 hr by immunofluorescent assay. When tested for capacity to discriminate between PUU, DOB, and HTN viruses, significant differences were found: the Swedish serum detected PUU antigen at high titers, whereas no reactivity was found against DOB and HTN; the Bosnian serum detected both DOB and HTN at high titers but had a low reactivity to PUU. The method was also tested for its usefulness in detecting PUU antigen in bank vole (clethrionomys glareolus) lungs. Of 59 animals captured from the surroundings of patients with nephropathia epidemica, three became positive with a high activity in the PUU-ELISA, but with low reactivity in the DOB/HTN-ELISA. It is concluded that a sensitive ELISA has been developed to detect different hantaviruses in cell culture and lungs of bank voles.

  • 2.
    Eriksson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lindgren, Theres
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Löfroth, Per-Olov
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells2008In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 23, no 5, p. 541-549Article in journal (Refereed)
    Abstract [en]

    Iodine-131 (131I) has been used both in unconjugated form and conjugated to antibody derivates (i.e., radioimmunotherapy; RIT) to treat malignant diseases. The mechanisms by which 131I-irradiation causes growth retardation are, however, inadequately understood. The aim of this study was to elucidate the sequential molecular and cellular events that initiate cell death in HeLa Hep2 cells exposed to 131I. In this paper, HeLa Hep2 cells were found to display a transient G2-M arrest following irradiation, but then reentered the cell cycle still containing unrepaired cellular damage. An increase of multipolar mitotic spindles, as well as a significant increase in centrosome numbers from 8.8% +/- 1.9% in controls to 54.7% +/- 2.2% in irradiated cells, was observed (p < 0.0001). A subsequent failure of cytokinesis caused the cells to progress into mitotic catastrophe. This was accompanied by the formation of giant cells with multiple nuclei, multilobulated nuclei, and an increased frequency of polyploidy cells. A fraction of the cells also displayed apoptotic features, including the activation of initiator caspases-2, -8, -9, and effector caspase-3, as well as cleavage of poly(ADP-ribose) polymerase, a cell-death substrate for active caspase-3. These findings demonstrate that mitotic catastrophes and the activation of a delayed type of apoptosis might be important mechanisms involved in cell death following the RIT of solid tumors with -emitting radionuclides, such as 131I.

  • 3.
    Eriksson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Löfroth, Per-Olov
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Apoptotic signalling in HeLa Hep2 cells following 5 Gy of cobalt-60 gamma radiation2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 11, p. 4361-4366Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The apoptotic signalling pathways involved in the delayed type of apoptosis occurring in HeLa Hep2 cells following radiation were investigated. MATERIALS AND METHODS: HeLa Hep2 cells were exposed to 5 Gy of cobalt-60 radiation. The activation of caspase-2, caspase-8, caspase-9 and effector caspase-3 was investigated by caspase assay plates and Western blots. Cleavage of poly (ADP-ribose) polymerase (PARP) was analysed on Western blots. HeLa Hep2 cells were irradiated with or without preincubation with inhibitors of protein synthesis (cycloheximide, CHX) and caspases, followed by TUNEL staining and caspase assay plate evaluation. RESULTS: Initiator caspases-2, -8, -9, and effector caspase-3, were found to be activated and PARP cleaved following irradiation. CHX completely inhibited the caspase activation and the associated apoptosis. Pretreatment with caspase-2 inhibitor indicated that caspase-2 was involved in the execution of the apoptosis. CONCLUSION: Activation of the apoptotic signalling pathways following irradiation of HeLa Hep2 cells includes components from the intrinsic as well as the extrinsic pathways and seems to require de novo protein synthesis.

  • 4.
    Eriksson, David
    et al.
    Umeå University, Faculty of Medicine, Clinical Microbiology, Immunology/Immunchemistry.
    Löfroth, Per-Olov
    Umeå University, Faculty of Medicine, Radiation Sciences, Radiation Physics.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Radiation Sciences, Radiation Physics.
    Åhlström Riklund, Katrine
    Umeå University, Faculty of Medicine, Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Clinical Microbiology, Immunology/Immunchemistry.
    Cell cycle disturbances and mitotic catastrophes in HeLa Hep2 cells following 2.5 to 10 Gy of ionizing radiation.2007In: Clin Cancer Res, ISSN 1078-0432, Vol. 13, no 18 Pt 2, p. 5501s-5508sArticle in journal (Refereed)
    Abstract [en]

    PURPOSE: Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors. The purpose of this study was to elucidate the sequential molecular and cellular events occurring in HeLa Hep2 cells exposed to such doses. METHODS: Dose-response curves, activation of cell cycle checkpoints, and mitotic behavior were investigated in HeLa Hep2 cells following 2.5- to 10-Gy irradiation by carrying out 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, Western blots, fluorescence-activated cell sorting analysis, and immunofluorescence stainings. Terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining was used to detect apoptosis. RESULTS: A G2-M arrest was shown by fluorescence-activated cell sorting analysis. p53 and p21 were found to be up-regulated but were not immediately related to the arrest. The G2-M arrest was transient and the cells reentered the cell cycle still containing unrepaired cellular damage. This premature entry caused an increase of anaphase bridges, lagging chromosomal material, and multipolar mitotic spindles as visualized by propidium iodide staining and immunofluorescence staining with alpha-tubulin and gamma-tubulin antibodies. Furthermore, a dose-dependent significant increase in centrosome numbers from 12.6+/-6.6% to 67+/-5.3% was identified as well as a dose-dependent increase of polyploid cells from 2.8+/-1.3% to 17.6+/-2.1% with the highest absorbed dose of 10 Gy. These disturbances caused the cells to progress into mitotic catastrophe and a fraction of these dying cells showed apoptotic features as displayed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling staining 5 to 7 days after irradiation. CONCLUSION: An absorbed dose of 2.5 to 10 Gy was shown to force HeLa Hep2 cells into mitotic catastrophe and delayed apoptosis. These might be important cell death mechanisms involved in tumor growth retardation following radioimmunotherapy of solid tumors.

  • 5.
    Eriksson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Radiation-induced cell death mechanisms2010In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 31, no 4, p. 363-372Article in journal (Refereed)
    Abstract [en]

    The main goal when treating malignancies with radiation therapy is to deprive tumor cells of their reproductive potential. One approach to achieve this is by inducing tumor cell apoptosis. Accumulating evidences suggest that induction of apoptosis alone is insufficient to account for the therapeutic effect of radiotherapy. It has become obvious in the last few years that inhibition of the proliferative capacity of malignant cells following irradiation, especially with solid tumors, can occur via alternative cell death modalities or permanent cell cycle arrests, i.e., senescence. In this review, apoptosis and mitotic catastrophe, the two major cell deaths induced by radiation, are described and dissected in terms of activating mechanisms. Furthermore, treatment-induced senescence and its relevance for the outcome of radiotherapy of cancer will be discussed. The importance of p53 for the induction and execution of these different types of cell deaths is highlighted. The efficiency of radiotherapy and radioimmunotherapy has much to gain by understanding the cell death mechanisms that are induced in tumor cells following irradiation. Strategies to use specific inhibitors that will manipulate key molecules in these pathways in combination with radiation might potentiate therapy and enhance tumor cell kill.

  • 6.
    Erlandsson, Ann
    et al.
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Eriksson, David
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Clinical Microbiology.
    Sundström, Birgitta Elisabeth
    In vivo clearing of idiotypic antibodies with antiidiotypic antibodies and their derivatives2006In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 43, no 6, p. 599-606Article in journal (Refereed)
    Abstract [en]

    At immunolocalization of experimental tumors, idiotypic monoclonal antibodies, such as TS1 against cytokeratin 8, can be used to carry and deposit in vivo terapeutics in the tumor. These carriers also remain in the circulation and may cause negative side-effects in other tissues. In this report, several derivatives of the antiidiotypic antibody alphaTS1 were produced and tested for their clearing capacity of the idiotypic carrier antibody TS1. Intact monoclonal alphaTS1, scFv of a alphaTS1 and alphaTS1 Fab'2 and fragments were produced by recombinant technology or by cleavage with Ficin. The scFv was tailored by use of the variable domain genes of the light and heavy chain from the hybridoma clone in combination with a (Gly4Ser)3-linker, followed by expression in E. coli. When tested for clearing capacity, the intact divalent antiidiotypic IgG was found to be the most efficient. The divalent and the monovalent Fab fragment also demonstrated significant clearing, but lower than the intact antiidiotypic IgG. The alphaTS1 scFv antibody when injected separately was not found to clear the idiotype, but could do so when preincubated with the idiotype. Rapid excretion and in vivo instability of this low molecular weight antibody fragment may be the major reasons. Similar results were obtained when the system was reversed and the 131I-labeled antiidiotype IgG was cleared with the idiotype fragment. It is concluded that both intact antiidiotypic IgG, and Fab'2 fragments are able to clear the idiotypic antibodies. The experimental data support the conclusion that the Fc parts from both the idiotype and the antiidiotype may contribute to this elimination.

  • 7. Erlandsson, Ann
    et al.
    Holm, Patrik
    Jafari, Rozbeh
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sundström, Birgitta E
    Functional mapping of the anti-idiotypic antibody anti-TS1 scFv using site-directed mutagenesis and kinetic analysis2010In: mAbs, ISSN 1942-0870, Vol. 2, no 6, p. 662-669Article in journal (Refereed)
    Abstract [en]

    Recombinant antibodies may be engineered to obtain improved functional properties. Functional mapping of the residues in the binding surfaces is of importance for predicting alterations needed to yield the desired properties. In this investigation, 17 single mutation mutant single-chain variable fragments (scFvs) of the anti-idiotypic antibody anti-TS1 were generated in order to functionally map amino acid residues important for the interaction with its idiotype TS1. Residues in anti-TS1 determined to be very important for the interaction were identified, Y32L, K50L, K33H, and Y52H, and they were distributed adjacent to a centrally located hydrophobic area, and contributed extensively to the interaction energy (≥2.5 kcal/mol) in the interaction. Quantitative ELISA assays, BIAcore technologies and three-dimensional surface analysis by modeling were employed to visualize the consequences of the mutations. The expression levels varied between 2 - 1,800 nM as determined by ELISA. All the 17 scFvs displayed higher dissociation rates (60 - 1,300 times) and all but two of them also faster association rates (1.3 - 56 times). The decrease in affinity was determined to be 1.6 - 12,200 times. Two of the mutants displayed almost identical affinity with the wild type anti-TS1, but with a change in both association and dissociation rates. The present investigation demonstrates that it is possible to generate a large panorama of anti-idiotypic antibodies, and single out a few that might be of potential use for future clearing and pre-targeting purposes of idiotypic-anti-idiotypic interactions.

  • 8. Jafari, Rozbeh
    et al.
    Holm, Patrik
    Sandegren, Jenny
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sundström, Birgitta E
    Localization of complexed anticytokeratin 8 scFv TS1-218 to HeLa HEp-2 multicellular tumor spheroids and experimental tumors2010In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 25, no 4, p. 455-463Article in journal (Refereed)
    Abstract [en]

    Recombinant single-chain fragment variable (scFv) antibodies with specificity to tumor antigens can be used to target tumors in vivo. The approach to use administration of complexes of idiotypic-anti-idiotypic scFvs when targeting tumors has not been tested earlier, and from a theoretical point it could contribute to longer in vivo circulation and improved targeting efficiency by dissociation, when in contact with the target antigen. In this study two models to evaluate the targeting efficiency of such complexes were used. HeLa HEp-2 tumor cells were grown as multicellular tumor spheroids (MCTS) and exposed to the antibody constructs in vitro. The behavior in vivo was tested in an in vivo tumor xenograft model. To increase the size of the anticytokeratin 8 scFv, TS1-218, complexes were formed between TS1-218 and its anti-idiotype, alphaTS1 scFv. The functionality of (125)I-labeled TS1-218 alone and in complex was studied in both models. The uptake patterns were similar in both models. The idiotypic TS1-218 was able to localize to the MCTS and xenografted tumors, both alone and in complex with alphaTS1 scFv. TS1-218 in complex, however, demonstrated a significantly higher uptake than the monomeric TS1-218 in both models (p < 0.0005 and p < 0.0089, respectively). When complexes were administered in vivo, a slower clearance and an increased tumor half-life could be observed. The present investigation indicates that administration of targeting antibodies, with initially blocked antigen-binding sites by complex formation with their anti-idiotypes, may improve targeting efficiency.

  • 9. Johansson, Amanda
    et al.
    Sandström, Per
    Ullén, Anders
    Erlandsson, Ann
    Sundström, Birgitta
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stability and immunoreactivity of the monoclonal anticytokeratin antibody TS1 after different degrees of iodination.1999In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 38, no 3, p. 329-334Article in journal (Refereed)
    Abstract [en]

    The immunoreactivity, stability and in vivo kinetics of an anticytokeratin 8 monoclonal antibody, TS1, were investigated following different degrees of labeling with 125I (0.2, 1 and 2-3 125I/TS1 MAb). By testing with ELISA, it was demonstrated that a high degree of iodination, i.e. > 2 125I/TS1, caused a rapid decrease in immunoreactivity to almost zero within 10 days. Furthermore, a complete degradation to low molecular weight fragments and free iodine was seen, as shown by SDS PAGE and autoradiography. The differently labeled radionuclide conjugates were injected into nude mice inoculated with HeLa Hep2 cells and tumor doses (estimated by MIRD formalism), tumor:non-tumor dose ratios, % I.D./gram tissue, Gy/MBq and in vivo kinetics of the differently labeled MAbs were determined. Despite the in vitro instability of the highest iodinated radionuclide conjugate, it was possible to deliver high doses to the tumors if the conjugate was injected into the animal immediately after completion of the iodination procedure. Increases from 1.4 Gy to 15.2 Gy delivered tumor dose were obtained with a tenfold increase in the specific activity, without alterations in the tumor:non-tumor tissue dose ratios. There is room for significant improvements in efficacy at radioimmunotherapy, which can be gained by optimizing the degree of iodination. For therapeutical applications a high degree of iodination may be an advantage.

  • 10. Le Du, Marie Hélène
    et al.
    Kozlenkov, Alexey
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Crilly, Karan S
    Llinas, Paola
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Menéz, André
    Stura, Enrico A
    Millán, José Luis
    Kiss, Zoltan
    Structural and functional analysis of a non-catalytic binding site in human placental alkaline phosphataseManuscript (Other academic)
  • 11.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Erikssom, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Alterations in gene expression during radiation induced mitotic catastrophe in HeLa Hep2 cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: To explore kinetic changes in the gene expression profile during radiation induced mitotic catastrophes.

    Methods and Materials: We measured temporal global gene expression in HeLa Hep2 tumor cells using bead chip arrays (Illumina) following exposure to 5 Gy of ionizing radiation (60Co). Genes with less than a 2-fold change in expression and a p-value > 0.05 were discarded. Signaling pathways significantly altered following irradiation were explored using Metacore. Furthermore, biological responses linked to mitotic catastrophe including cell cycle arrests, anaphase bridge formation and centrosome amplification were analyzed and correlation to gene expression changes evaluated.

    Results: Following irradiation a G2-arrest was induced. This arrest was transient and cells entered mitosis before DNA damage was repaired causing anaphase bridge formation. Furthermore, radiation induced hyperamplification of centrosomes was observed. These phenotypical changes correlated well with the observed gene expression changes. At 6 h following irradiation the expression was changed only for a few genes including histone H2 and H4, essential for activation of a DNA-damage checkpoint. Striking changes appeared at later time-points. From 12-96 hours post irradiation a significant fraction of the genes with altered expression were found to be involved in cell cycle progression and its regulation. The significant changes were seen for genes important for several mitotic processes, and those involved in the G2- and spindle assembly checkpoints. Also centrosome associated genes displayed an increased expression. Furthermore, 96 hours after irradiation pathways involved in immune and inflammatory responses were significantly altered.

    Conclusions: This study elucidates specific characteristics in the altered gene expression pattern induced by irradiation, which can be linked to the sequential steps observed in HeLa Hep2 cells during mitotic catastrophes. Therapeutic strategies employing these alterations might potentiate future therapy and enhance tumor cell killing.

  • 12.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Alterations in Gene Expression During Radiation-Induced Mitotic Catastrophe in He La Hep2 Cells2014In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 34, no 8, p. 3875-3880Article in journal (Refereed)
    Abstract [en]

    Aim: To explore kinetic changes in the gene expression profile during radiation-induced mitotic catastrophes. Materials and Methods: Gene expression changes were measured in HPV-infected HeLa Hep2 tumor cells following exposure to 5 Gy of ionizing radiation (Co-60). Signaling pathways were explored and correlated to the biological responses linked to mitotic catastrophe. Results: Following irradiation a transient G(2)-arrest was induced. Anaphase bridge formation and centrosome hyperamplification was observed. These phenotypical changes correlated well with the observed gene expression changes. Genes with altered expression were found to be involved in mitotic processes as well as G(2)- and spindle assembly checkpoints. Also centrosome-associated genes displayed an increased expression. Conclusion: This study elucidates specific characteristics in the altered gene expression pattern induced by irradiation, which can be correlated to the events of mitotic catastrophe in HeLa Hep2 cells. Therapeutic strategies modulating these alterations might potentiate future therapy and enhance tumor cell killing.

  • 13.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Raberg, A
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Eriksson, David
    Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT 116 cell lines2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no Suppl. 1, p. 76-76Article in journal (Other academic)
  • 14.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Gene expression profiling in MOLT-4 cells during gamma-radiation-induced apoptosis2012In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 33, no 3, p. 689-700Article in journal (Refereed)
    Abstract [en]

    This study aims to identify the temporal changes in gene expression in MOLT-4, a leukemia cell line, in response to radiation and to present a comprehensive description of the pathways and processes that most significantly relate to the cellular biological responses. A global gene expression profile of 24,500 genes was performed on MOLT-4 tumor cells following exposure to 5 Gy of ionizing radiation (Co-60) using a bead chip array (Illumina). Signaling pathways and processes significantly altered following irradiation were explored using MetaCore. Cellular viability [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], activation of cell cycle checkpoints [fluorescence activated cell sorting (FACS)], and induction of apoptosis (FACS, caspase assays) were evaluated to correlate these biological responses to the gene expression changes. Totally, 698 different genes displayed a significantly altered expression following radiation, and out of these transcripts, all but one showed increased expression. One hour following irradiation, the expression was changed only for a few genes. Striking changes appeared at later time-points. From 3 to 24 h post-irradiation, a significant fraction of the genes with altered expression were found to be involved in cell cycle checkpoints and their regulation (CDKN1A), DNA repair (GADD45A, DDB2, XPC), apoptosis induction (DR5, FasR, Apo-2L, Bax), and T-cell activation/proliferation (CD70, OX40L). Irradiated MOLT-4 cells were arrested at the G2-checkpoint, followed by a decrease in cell viability, most pronounced 48 h after exposure. The cell death was executed by induced apoptosis and was visualized by an increase in subG1 cells and an increased activation of initiator (caspase-8 and caspase-9) and execution (caspase-3) caspases. Activation of cell cycle arrest and apoptosis correlated well in time with the changes in gene expression of those genes important for these biological processes. Activation of the apoptotic signaling pathways in MOLT-4 cells following irradiation includes components from the intrinsic as well as the extrinsic apoptotic pathways. This study indicates that the altered gene expression pattern induced by irradiation is important for the sequential steps observed in MOLT-4 cells during apoptosis induction.

  • 15.
    Lindgren, Theres
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Råberg, Aino
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Genome wide expression analysis of radiation induced DNA damage responses in isogenic HCT116 p53 +/+ and HCT116 p53 -/- colorectal carcinoma cell lines2015In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 91, no 1, p. 99-111Article in journal (Refereed)
    Abstract [en]

    Purpose : To study the kinetics of gene expression alterations following radiation exposure of isogenic HCT116 p53+/+ and HCT116 p53-/- cell lines. Materials and methods : Cells were exposed to 5 Gy of irradiation (Cs-137) and genome-wide temporal expression analysis using Illumina bead chip arrays was performed. Signalling pathways were explored using Metacore (Genego). Biological responses including cell cycle checkpoint activation, centrosome amplification and senescence induction were analyzed. Results : Significant differences in the radiation response were observed between the p53+/+ and the p53-/- cell lines. In p53+/+ cells concurrent G1- and G2-arrests were activated followed by senescence induction. Increased expression of genes associated with senescence, senescence associated secretory phenotype (SASP) and repression of genes essential for G2-M transition were detected. P53-/- cells arrested mainly in G2 followed by centrosome amplification, mitotic slippage and a subsequent increase of polyploid cells. Furthermore, changes in expression correlated well with these signs of mitotic catastrophe. Conclusions : The presence or absence of p53 triggers different signalling cascades with different endpoints. Elucidating these differences is important as it enables improvement of radiation treatment and could be used to develop new combination treatments with specific inhibitors of key regulators of these cell death modalities.

  • 16. Llinas, Paola
    et al.
    Stura, Enrico A
    Ménez, André
    Kiss, Zoltan
    Stigbrand, Torgny
    Millán, José Luis
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Le Du, Marie Hélène
    Structural studies of human placental alkaline phosphatase in complex with functional ligands.2005In: J Mol Biol, ISSN 0022-2836, Vol. 350, no 3, p. 441-51Article in journal (Refereed)
  • 17. Mirzaie-Joniani, Homa
    et al.
    Eriksson, David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Johansson, Amanda
    Löfroth, Per-Olov
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Åhlström-Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Apoptosis in HeLa Hep2 cells is induced by low-dose, low-dose-rate radiation.2002In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 158, no 5, p. 634-640Article in journal (Refereed)
  • 18.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Karlsson, Jan Erik
    Rosengren, Lars
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Monoclonal antibodies selective for low molecular weight neurofilaments2002In: Hybridoma and Hybridomics, ISSN 1536-8599, Vol. 21, no 1, p. 53-59Article in journal (Refereed)
    Abstract [en]

    Neurofilaments are necessary for the maintenance of axonal caliber and structural organization of nerve cells. The low molecular weight form of neurofilament, the neurofilament light protein, which serves as the core of the filament, was used as immunogen for generation of hybridomas with selective reactivity with this form of the filament. Six hybridomas, out of approximately 100 tested clones, were highly discriminatory. All involved epitopes were localized to the rod region of the antigen, as determined by alpha-chymotrypsin digestion of the purified filament and enzymatic peptide mapping. Synthetic peptides (20 mers) covering the entire rod region did not react with the antibodies. A phage display peptide library was used to identify four consensus sequences for the antibodies. The results indicate that all epitopes were of conformational type. Pair-wise BIAcore data furthermore indicated that the epitopes were independent. The access to such specific reagents is a prerequisite for further elucidation of the biology of the low molecular weight form of neurofilaments proteins.

  • 19.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rosengren, Lars
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Elevated neurofilament levels in neurological diseases2003In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 987, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    Neurofilaments, a major cytoskeletal constituent of neuronal cells, can be released into the cerebrospinal fluid during several neurodegenerative diseases. By means of a new sensitive ELISA capable of measuring 60 ng/l of neurofilament light, significant elevations were observed for different neurological disorders. Cerebral infarction presented levels of 19800+/-9100 ng/l, amyothropic lateral sclerosis 3600+/-1200 ng/l, 'relapsing-remitting' MS 2500+/-1500 ng/l, extrapyramidal symptoms 1100+/-300 ng/l, late onset AD 300+/-100 ng/l and vascular dementia 1400+/-800 ng/l. In patients with no signs of neurological diseases the upper normal level and cut-off values was determined to be below 100 ng/l. NF-L determinations will be a valuable complement in identifying neuronal degradation and can be used clinically for diagnostic and monitoring purposes.

  • 20.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Cerebrospinal fluid levels of neurofilament light in chronic experimental autoimmune encephalomyelitis2005In: Brain Research Bulletin, ISSN 0361-9230, E-ISSN 1873-2747, Vol. 67, no 4, p. 264-268Article in journal (Refereed)
    Abstract [en]

    Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) is a chronic relapsing-remitting animal model of multiple sclerosis (MS). Neurofilament light (NF-L), a structural protein expressed in neuronal cells can be used to quantify the amount of neuronal damage in MS patients. An immunoassay was used to measure levels of neurofilament light in cerebrospinal fluid (CSF) in rats with myelin oligodendrocyte glycoprotein-induced EAE. Significantly increased levels of neurofilament were found in the immunized animals compared to the controls, strengthening the similarities in the diseases and the progression pattern between the animal model and MS. The turnover of NF-L during this disease is increased since significantly elevated levels also were identified in the spinal cord of the diseased animals and immunohistochemistry gave support for this observation. Monitoring neurofilament levels in EAE can be used to follow disease progression and effects of therapy.

  • 21.
    Norgren, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Rosengren, Lars
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Gunnarsson, Martin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Neurofilament light and glial fibrillary acidic protein in multiple sclerosis2004In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 63, no 9, p. 1586-1590Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) in CSF from patients with multiple sclerosis (MS) in relation to clinical progress of the disease.

    Methods: CSF levels of NFL and GFAP were determined by sensitive ELISAs in 99 patients with different subtypes of MS, classified in terms of “ongoing relapse” or “clinically stable disease,” and 25 control subjects. Levels were compared with paraclinical data such as immunoglobulin G index and inflammatory cell count in the CSF, and the levels were related to Expanded Disability Status Scale score and progression index at clinical follow-up evaluations later in the disease course.

    Results: NFL and GFAP levels were elevated in MS patients as compared with control subjects (p < 0.001). The NFL levels were higher at relapses, whereas GFAP levels were unaffected. High NFL levels correlated with progression in patients with an active relapse (r = 0.49; p < 0.01) and in clinically stable patients (r = 0.29; p < 0.05). GFAP correlated to progression in the total patient cohort (r = 0.24; p < 0.05). Moreover, a strong correlation between NFL levels and inflammatory cell counts was evident in the group of patients with an ongoing relapse (r = 0.52; p = 0.001).

    Conclusions: CSF levels of neurofilament light and glial fibrillary acidic protein may have prognostic value in multiple sclerosis.

  • 22. Paus, Elisabeth
    et al.
    Haugen, Mads Haugland
    Olsen, Kari Hauge
    Flatmark, Kjersti
    Maelandsmo, Gunhild Mari
    Nilsson, Olle
    Röijer, Eva
    Lundin, Maria
    Fermér, Christian
    Samsonova, Maria
    Lebedin, Yuri
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    TD-11 workshop report: characterization of monoclonal antibodies to S100 proteins2011In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 32, no 1, p. 1-12Article in journal (Refereed)
    Abstract [en]

    Fourteen monoclonal antibodies with specificity against native or recombinant antigens within the S100 family were investigated with regard to immunoreactivity. The specificities of the antibodies were studied using ELISA tests, Western blotting epitope mapping using competitive assays, and QCM technology. The mimotopes of antibodies against S100A4 were determined by random peptide phage display libraries. Antibody specificity was also tested by IHC and pair combinations evaluated for construction of immunoradiometric assays for S100B. Out of the 14 antibodies included in this report eight demonstrated specificity to S100B, namely MAbs 4E3, 4D2, S23, S53, 6G1, S21, S36, and 8B10. This reactivity could be classified into four different epitope groups using competing studies. Several of these MAbs did display minor reactivity to other S100 proteins when they were presented in denatured form. Only one of the antibodies, MAb 3B10, displayed preferential reactivity to S100A1; however, it also showed partial cross-reactivity with S100A10 and S100A13. Three antibodies, MAbs 20.1, 22.3, and S195, were specific for recombinant S100A4 in solution. Western blot revealed that MAb 20.1 and 22.3 recognized linear epitopes of S100A4, while MAb S195 reacted with a conformational dependent epitope. Surprisingly, MAb 14B3 did not demonstrate any reactivity to the panel of antigens used in this study.

  • 23. Petzold, Axel
    et al.
    Altintas, Ayse
    Andreoni, Laura
    Bartos, Ales
    Berthele, Achim
    Blankenstein, Marinus A
    Buee, Luc
    Castellazzi, Massimiliano
    Cepok, Sabine
    Comabella, Manuel
    Constantinescu, Cris S
    Deisenhammer, Florian
    Deniz, Gunnur
    Erten, Gaye
    Espiño, Mercedes
    Fainardi, Enrico
    Franciotta, Diego
    Freedman, Mark S
    Giedraitis, Vilmantas
    Gilhus, Nils Erik
    Giovannoni, Gavin
    Glabinski, Andrzej
    Grieb, Pawel
    Hartung, Hans-Peter
    Hemmer, Bernhard
    Herukka, Sanna-Kaisa
    Hintzen, Rogier
    Ingelsson, Martin
    Jackson, Samuel
    Jacobsen, Steve
    Jafari, Naghmeh
    Jalosinski, Marcin
    Jarius, Sven
    Kapaki, Elisabeth
    Kieseier, Bernd C
    Koel-Simmelink, Marleen J A
    Kornhuber, Johannes
    Kuhle, Jens
    Kurzepa, Jacek
    Lalive, Patrice H
    Lannfelt, Lars
    Lehmensiek, Vera
    Lewczuk, Piotr
    Livrea, Paolo
    Marnetto, Fabiana
    Martino, Davide
    Menge, Til
    Norgren, Niklas
    UmanDiagnostics, Umea Biotech Incubator, Tvistevägen 48, SE-90736 Umea, Sweden.
    Papuć, Eva
    Paraskevas, George P
    Pirttilä, Tuula
    Rajda, Cecília
    Rejdak, Konrad
    Ricny, Jan
    Ripova, Daniela
    Rosengren, Lars
    Ruggieri, Maddalena
    Schraen, Susanna
    Shaw, Gerry
    Sindic, Christian
    Siva, Aksel
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stonebridge, Iva
    Topcular, Baris
    Trojano, Maria
    Tumani, Hayrettin
    Twaalfhoven, Harry A M
    Vécsei, László
    Van Pesch, Vincent
    Vanderstichele, Hugo
    Vedeler, Christian
    Verbeek, Marcel M
    Villar, Luisa Maria
    Weissert, Robert
    Wildemann, Brigitte
    Yang, Cui
    Yao, Karen
    Teunissen, Charlotte E
    Neurofilament ELISA validation2010In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 352, no 1-2, p. 23-31Article in journal (Refereed)
    Abstract [en]

    This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online.

  • 24.
    Riklund, Katrine
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Edbom, Göran
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Makiya, R
    Johansson, B
    Gerdes, U
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ekelund, Leif
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Stendahl, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Radioimmunoscintigraphy of gynecologic tumors with 131I-labeled anti-PLAP monoclonal antibodies.1991In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 32, no 5, p. 375-380Article in journal (Refereed)
    Abstract [en]

    Radioimmunoscintigraphy (RIS) was performed in 20 patients with gynecologic tumors, 14 ovarian, 5 cervical, and one endometrial carcinoma. One murine monoclonal antibody (mab) against placental alkaline phosphatase (H7) was used after radiolabeling with 131I. The labeling procedure yielded antibodies with specific activity varying between 60 and 73 MBq/mg mab. Each patient received 57 to 100 MBq of the preparation. RIS was performed 7 to 35 days later. Patients with ovarian adenocarcinoma had an accumulation of activity on RIS at tumor sites (79%, 11/14) verified by ultrasonography, CT, and clinical examination. A low or absent accumulation of activity was seen in patients with cervical tumors. The patient with an endometrial adenocarcinoma was seen to have an activity accumulation at RIS corresponding to tumor sites determined by ultrasound and/or CT. It is concluded that RIS using monoclonal antibodies against placental alkaline phosphatase can provide information which will supplement that gained from other investigations of patients with ovarian adenocarcinomas.

  • 25.
    Riklund, Katrine
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stendahl, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Radioimmunodetection of ovarian cancer.1993In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 32, no 7-8, p. 729-734Article in journal (Refereed)
    Abstract [en]

    Radioimmunoscintigraphy (RIS) is a potentially valuable method for the detection of primary, secondary and recurrent malignant tumours. Antigens that have been used for monitoring as well as for RIS of ovarian carcinomas include CA 125, PLAP, HMFG, and CA 19-9. Between 70 and 100% of the tumours have been detected at RIS when these antigens have been used. Conventional methods, e.g., computerized tomography (CT) and ultrasonography (US), demonstrate similar or lower detection rate than RIS for tumour diagnosis. RIS gives additional information to conventional radiological methods (CT and US) for the detection of occult ovarian carcinomas. A review of earlier investigations is given and our own recent results using PLAP as a target antigen are presented. The future potential of the technology is discussed.

  • 26.
    Riklund, Katrine
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Makiya, R A
    Sundström, B E
    Thornell, L E
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Experimental radioimmunotherapy of HeLa tumours in nude mice with 131I-labeled monoclonal antibodies.1990In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 10, no 2A, p. 379-84Article in journal (Refereed)
    Abstract [en]

    The radioimmunotherapeutic potential of 131I-labeled monoclonal antibodies was investigated in 36 nude mice (BALB/c nu/nu) inoculated s.c. with the HeLa Hep 2 human adenocarcinoma cell line. The membrane bound tumour associated antigen placental alkaline phosphatase and several intracellular cytokeratins served as targets for the antibodies. The specific radioactivity in each organ was determined after i.p. injection of the 131I-labeled antibodies (0.2-0.3 mg, approximately 15 MBq/animal), and high localization to the tumours was seen. Significant growth inhibition was observed after injection of the radiolabeled monoclonal antibody H7 against the placental alkaline phosphatase, which reduced the tumour growth to only 12% during a 3 week period compared to a growth of more than 100% for the controls. Animal weight losses were seen. Synthesis of endogenous antibodies to the target antigens was found to be significant. Morphometric evaluation of the relations between stroma, tumour cells and necrotic areas in the tumours after radioimmunotherapy demonstrated a significant increase of the mean relative connective tissue volume and a significant decreased mean of relative volume of tumour cells in the group treated with iodinated antiplacental alkaline phosphatase antibody. This therapeutic principle is encouraging and may offer new possibilities for future treatment of some malignant diseases.

  • 27.
    Riklund, Katrine
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Makiya, R E
    Ullén, A P
    Damber, Jan Erik
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    A putative mechanism for the non-specific uptake of intact radiolabelled monoclonal antibodies in the testes and prostate.1996In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 35, no 3, p. 303-307Article in journal (Refereed)
    Abstract [en]

    Non-specific testicular accumulation of radiolabelled intact anti-CEA monoclonal antibody (MAb), (A431/26, Behringwerke AG) was observed in 11 out of 12 patients with the testes and prostate included in the examination field at radioimmunoscintigraphy (RIS). Previous studies have shown that placental alkaline phosphatase (PLAP) serves as an Fc-receptor, mediating IgG transport through the placenta. A closely related protein, the germ cell alkaline phosphatase (GCAP), is expressed in the testes. The testicular uptake of IgG is observed only when intact but not fragmented MAbs are used, indicating involvement of Fc-receptors. MDCK cells (dog kidney cell line) transfected with the plasmid pSVT7 containing the GCAP gene were shown to acquire the capacity to both express membrane bound GCAP and to bind IgG on the cell surface. This might indicate that GCAP is responsible for the non-specific accumulation of intact MAb in the testes and prostate often observed when intact murine MAbs are used for radioimmunolocalization (RIL).

  • 28.
    Riklund, Katrine
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Makiya, R
    Sundström, B
    Bäck, O
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Inhibition of growth of HeLa cell tumours in nude mice by 125I-labeled anticytokeratin and antiPLAP monoclonal antibodies.1991In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 11, no 2, p. 555-560Article in journal (Refereed)
    Abstract [en]

    The radiommunotherapeutic potential of 125I-labeled monoclonal antibodies was investigated in 48 nude mice (BALB/c, nu/nu) inoculated s.c. with the HeLa Hep 2 human adenocarcinoma cell line. This isotope, 125I, which is not commonly used for therapeutic purposes caused significant decrease in tumour growth from day 10 to day 42, when coupled to monoclonal antibodies directed against placental alkaline phosphatase (H7) or cytokeratins (TS1). The average growth rate was approximately 50-60% of that observed in the untreated control group after 42 days. The specific radioactivity in each organ 42 days after injection of radiolabeled monoclonal antibodies, indicated that these target antigens retain significant amounts of radiolabeled antibody in the tumours for at least 6 weeks after injection. No weight loss was seen in the animals during this experiment. By use of autoradiographic techniques, the labeled monoclonal antibodies were visualized deep in tumours in characteristic patterns representative of viable tumour cells (H7) and necrotic areas (TS1). The therapeutic approach using 125I labeled antibodies is encouraging and may offer new dimensions in radioimmunotherapy.

  • 29.
    Rolandsson, Olov
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Riklund Åhlström, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Eary, J
    Greenbaum, C
    Accumulation of(125)iodine labeled interleukin-2 in the pancreas of NOD mice.2001In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 17, no 4, p. 281-287Article in journal (Refereed)
    Abstract [en]

    Interleukin-2 (IL-2) is an important cytokine in the autoimmune process proceeding Type 1 diabetes. Our aim was to investigate, in two previously used animal models, the NOD mouse and the BB/W rat, the in vivo tissue distribution of radio-labeled IL-2. If the radio-labeled IL-2 accumulated significantly in the pancreas compared to surrounding organs it could allow imaging of lymphocyte infiltration of the islets of Langerhans by scintigraphic methods. IL-2 was labeled enzymatically with(125)Iodine. Radio-labeled IL-2 was injected iv in prediabetic NOD mice, diabetic NOD mice and Balb/c mice in the first animal model and in BB rats in the second model. Animals were sacrificed at different time points and the activity in different organs was measured. It was found that the mean activity in the pancreas in both diabetic and prediabetic NOD mice was significantly higher compared to pancreas from Balb/c mice (P< 0.001 and P=0.005, respectively). However, the mean activity in the pancreas was at the lower range of the surrounding organs in both animal models, thereby excluding the possibility of imaging the autoimmune process by scintigraphic methods. It is concluded that radio-labeled IL-2 did accumulate significantly in the pancreas of NOD mice compared to control mice but there is a need to develop new techniques in order to visualize the localized activity.

  • 30. Rossi Norrlund, Rauni
    et al.
    Ullén, Anders
    Sandström, Per
    Holback, Daniel
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Dosimetry of fractionated experimental radioimmunotargeting with idiotypic and anti-idiotypic anticytokeratin antibodies.1997In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 80, no 12 Suppl, p. 2681-2688Article in journal (Refereed)
    Abstract [en]

    The fractionated strategy can contribute to a significant accumulation of radiolabeled TS1 in the tumors. Furthermore, the use of alphaTS1 makes it possible to increase the tumor-to-nontumor dose ratio and maintain a prolonged high activity accumulation in the tumor.

  • 31. Rossi Norrlund, Rauni
    et al.
    Ullén, Anders
    Sandström, Per
    Holback, Daniel
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Experimental radioimmunotargeting combining nonlabeled, iodine-125-labeled, and anti-idiotypic anticytokeratin monoclonal antibodies: a dosimetric evaluation.1997In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 80, no 12 Suppl, p. 2689-2698Article in journal (Refereed)
    Abstract [en]

    This study confirms an extensive accumulation of TS1 in the tumor, with peak values as late as 30 days after injection of labeled TS1. Furthermore, both preinjection of nonlabeled TS1 and postinjection of alphaTS1 can improve radioimmunotargeting.

  • 32.
    Rydh, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nilsson, Sten
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Damber, Jan Erik
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Radioimmunotherapy of DU-145 tumours in nude mice--a pilot study with E4, a novel monoclonal antibody against prostate cancer.1999In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 38, no 8, p. 1075-1079Article in journal (Refereed)
    Abstract [en]

    The anti-tumour effect of the 131I-labelled antiprostate monoclonal antibody (MAb) E4 was studied in an experimental model with 41 nude mice, subcutaneously xenografted with a human prostate cancer cell line (DU-145). The mice were divided into four study groups, i.e. one receiving single and another repeated injections of the radiolabelled MAb. A third group was injected with non-labelled MAb, and the fourth served as an untreated control group. The tumour volumes increased similarly in all groups during the 27-day observation period. The tumour tissue was morphologically disintegrated in the group that received repeated radioimmunotherapy (RIT). The tumours from this group contained large fluid-filled cystic parts and demonstrated pronounced cellular and subcellular polymorphism in the remaining viable tumour tissue. The untreated control tumours and single therapy tumours remained solid. The proportion of the total tumour volume that consisted of viable tumour cells, as determined by morphometric techniques, was significantly lower in the 131I-E4-treated groups. The use of 131I-labelled E4 MAb has thus demonstrated a promising therapeutic potential.

  • 33. Rye, Phil D
    et al.
    Rittenhouse, Harry
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Up close and personal: molecular diagnostics in oncology2004In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 25, no 4, p. 217-220Article in journal (Refereed)
    Abstract [en]

    The almost overwhelming volume of information and new technological developments that has demanded so much of our scientific attention over the last decade will shortly revolutionize clinical diagnostics. Some of these developments are already affecting the working lives of scientists and clinicians alike, but will eventually require a greater understanding and acceptance from a much wider audience. Therefore it is important in our current scientific endeavor and commercial enthusiasm for molecular diagnostics that we maintain some awareness of the significant obstacles that must be overcome if we are to see an appropriate, timely and widespread adoption of molecular diagnostic testing in oncology. This article presents a brief commentary on the current state of the art in molecular diagnostics in oncology and how this relates to a more personalized approach to treatment.

  • 34. Rye, Phil D
    et al.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Interfering with cancer: a brief outline of advances in RNA interference in oncology2004In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 25, no 5-6, p. 329-336Article in journal (Refereed)
    Abstract [en]

    RNA interference (RNAi) is a potent and ubiquitous gene-silencing mechanism that is generating considerable excitement in the fields of molecular biology and gene therapy. It is now in widespread use for loss-of-function analysis in many diseases including cancer. Nevertheless, RNAi is still in its infancy, with new discoveries appearing on a monthly basis. This article presents a brief outline of the history and recent advances in RNAi with a specific focus on its potential in oncology.

  • 35. Rye, Phil D
    et al.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    The bioinformatic catalyst in the kallikrein family2004In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 25, no 5-6, p. 327-328Article in journal (Refereed)
  • 36. Sandström, Per
    et al.
    Johansson, Amanda
    Ullén, Anders
    Rathsman, Sandra
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Idiotypic-anti-idiotypic antibody interactions in experimental radioimmunotargeting.1999In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 5, no 10 Suppl, p. 3073s-3078sArticle in journal (Refereed)
    Abstract [en]

    Idiotypic-anti-idiotypic antibody interactions can be used in vivo to regulate the serum levels of specific radiolabeled antibodies. Anti-idiotypic antibodies can also be used as clearing agents for radiolabeled antibodies in radioimmunolocalization and radioimmunotherapy. The present study describes the immunochemical interactions between the monoclonal idiotype (H7) and three generated monoclonal anti-idiotypic antibodies (alphaH7:1, alphaH7:35, and alphaH7:38). An unexpected variability in complex formation could be demonstrated in vitro, revealing three different stable complex patterns, i.e., low molecular weight 1:1 complexes, ladder formation with oligomeric, consecutively added constituents, and large linear polymeric complexes of high molecular weight. Within 24 h, the anti-idiotypes were able to cause a significant decrease in total body radioactivity, and the antibody generating a ladder formation (alphaH7:38) was found to be the most efficient at removing radiolabeled idiotypes from the circulation. It is concluded that monoclonal anti-idiotypic antibodies may be valuable tools in improving radioimmunolocalization and radioimmunotargeting.

  • 37.
    Smans, Karine A
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ingvarsson, Magdalena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindgren, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Canevari, Silvana
    Walt, Heinrich
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Millán, José Luis
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Bispecific antibody-mediated lysis of primary cultures of ovarian carcinoma cells using multiple target antigens1999In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 83, no 2, p. 270-277Article in journal (Refereed)
    Abstract [en]

    We have shown previously that a bispecific antibody (BsAb) directed against both germ-cell alkaline phosphatase (GCAP) and the CD3 complex on mouse T cells could effectively eliminate GCAP-positive tumor cells in vivo using an immunocompetent mouse model. However, some GCAP-negative tumor cells were still able to grow, suggesting that BsAb therapy, when used in a clinical setting, could benefit from targeting several tumor markers to prevent outgrowth of tumor cells lacking a targeted marker. To test this hypothesis, we developed an in vitro model based on primary human ovarian carcinoma (OC) cultures and BsAbs directed against human T cells and several tumor markers [placental alkaline phosphatase (PLAP), GCAP, folate-binding protein (FBP) and CA19.9]. OC cells, isolated from primary tumors, were co-cultured with human peripheral blood mononuclear cells in the presence or absence of various concentrations of BsAbs against PLAP/GCAP, FBP and CA19.9 administered separately or in combination. Results derived from 18 primary OC samples showed that the combination treatment was better than or equally effective as the best single BsAB treatment in 60% of cases. Sometimes targeting FBP, PLAP/GCAP or CA19.9 alone was superior to targeting all simultaneously. Combining each BsAb with a low dose of IL-2 was always beneficial. These results indicate that before using a specific BsAb in the clinic, it is important to determine the optimal BsAb for each patient using this in vitro assay on cells from the removed tumor mass.

  • 38.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Purification and properties of umecyanin: a novel intensely blue copper protein from horseradish root1971Doctoral thesis, comprehensive summary (Other academic)
  • 39.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    The rapidly changing landscape of scientific publishing2017Other (Other (popular science, discussion, etc.))
  • 40.
    Stigbrand, Torgny
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Johansson, B
    Makiya, R
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ekelund, Leif
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Tumour radioimmunolocalization in nude mice by use of antiplacental alkaline phosphatase monoclonal antibodies.1989In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 10, no 5, p. 243-251Article in journal (Refereed)
    Abstract [en]

    Three monoclonal antibodies and their Fab and Fab'2 fragments with specificity against human placental alkaline phosphatase (PLAP) were evaluated for tumour immunolocalization of human PLAP-producing Hela Hep 2 tumours in nude mice. The antibodies and their fragments were labelled with 125I and injected intraperitoneally in mice with developing Hep 2 tumours. The animals were followed individually for 14 days with repetitive computerized gamma-camera recordings, which enable quantitation of several crucial parameters, i.e. the time-dependent antibody uptake in the tumours, decrease in background activity and tumour/background ratio. Excellent radioimmunolocalization was obtained with both the intact PLAP-specific immunoglobulins and their fragments but not with the nonspecific antibodies. No background subtraction had to be used. As much as 15% of the initially injected dose could be visualized in the tumours and for the uncleaved mab up to 80% of the radioactivity in the animals was retained in the tumours after 14 days, a considerably longer observation time than usually reported in such tumour xenograft models. The Fab and Fab'2 fragments were found to be excreted fast with less than 5% of the injected dose remaining in the animals after 48 h, but still with positive specific localization to the tumours after an initial high uptake in the kidneys. The results are encouraging and indicate significant potentials of the PLAP-antiPLAP mab system for immunolocalization studies in patients.

  • 41.
    Stigbrand, Torgny
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Välkomna till 2013 års Forskningens dag!2013In: Cancerforskning på nya vägar: en bok från Forskningens dag 2013, Medicinska fakulteten vid Umeå universitet / [ed] Mattias Grundström Mitz och Lena Åminne, Umeå: Umeå universitet , 2013, 1, p. 7-14Chapter in book (Other (popular science, discussion, etc.))
  • 42.
    Stigbrand, Torgny
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sundström, B
    Makiya, R
    Stendahl, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Alternative technologies to generate monoclonal antibodies.1993In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 32, no 7-8, p. 841-844Article in journal (Refereed)
    Abstract [en]

    Several new technologies to generate and modify established hybridomas that produce monoclonal antibodies have recently been presented and further development should make them more suitable for diagnostic and therapeutic techniques. Different proteolytic procedures have been used for the fragmentation of intact antibodies to Fab2' and Fab fragments and recombinant DNA techniques have made it possible to obtain chimeric, humanized, Fv fragments and single-chain Fvs. A review of the new approaches is presented and the future implications are discussed.

  • 43.
    Stigbrand, Torgny
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Tholander, B
    Hirano, K
    Lalos, O
    Stendahl, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Placental alkaline phosphatase (PLAP)/PLAP-like alkaline phosphatase as tumour marker in relation to CA 125 and TPA for ovarian epithelial tumours.1990In: European journal of gynaecological oncology, ISSN 0392-2936, Vol. 11, no 5, p. 351-360Article in journal (Refereed)
    Abstract [en]

    The significance of the PLAP (Placental alkaline phosphatase)/PLAP-like isozyme as tumour marker in relation to CA 125 and TPA for the monitoring of patients with malignant ovarian epithelial tumours was evaluated. Of all patients (n = 85), 40% had all three markers elevated. CA 125 being the most sensitive (60%), and the PLAP/PLAP-like isozyme and TPA both 40%. A tendency to certain tumour marker patterns of these three antigens in serum can be seen with regard to histopathology. Serous and anaplastic adenocarcinomas usually have all three markers moderately elevated, mucinous and mesonephric adenocarcinomas both have low incidences and low average levels of all three markers. Endometrioid and non-mucinous adenocarcinomas are often associated with high levels of the PLAP/PLAP-like isozyme and CA 125, while TPA shows moderate elevation. The PLAP/PLAP-like isozyme is positively correlated to tumour burden and the outcome of the disease. It may provide additional information on CA 125 in the monitoring of patients with ovarian cancer.

  • 44.
    Stigbrand, Torgny
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ullén, Anders
    Sandström, P
    Mirzaie-Joniani, Homa
    Sundström, B
    Nillson, B
    Ärlestig, L
    Norrlund, R R
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Twenty years with monoclonal antibodies: State of the art--Where do we go?1996In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 35, no 3, p. 259-265Article in journal (Refereed)
    Abstract [en]

    In this review, we have selected some parameters with the potential to improve the efficacy of RIL and RIT. Focus has partially been on the behaviour of radiolabelled antibodies in vivo in relation to properties and amounts of both target antigen and the antibodies used. If, out of the 28 factors listed in Table 1, some should be given preference in future work, it is our opinion that after the initial saturation of the tumour site a rapid decrease in redundant antibody is of significant importance. Furthermore, quantitative aspects of both antigens and antibodies should be more carefully evaluated when possible. By combining several of the listed approaches toward increasing efficiency, a more extensive use of RIL and RIT could be expected in the future.

  • 45. Ullén, A
    et al.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Makiya, R
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Syngeneic anti-idiotypic antibodies eliminate excess radiolabeled idiotypes at experimental radioimmunolocalization.1995In: Cell biophysics, ISSN 0163-4992, Vol. 27, no 1, p. 31-45Article in journal (Refereed)
    Abstract [en]

    Significant improvements in tumor/nontumor ratio can be achieved by injections of nonlabeled anti-idiotypic monoclonal antibodies (MAbs) during radioimmunolocalization and radioimmunotherapy using MAbs to target experimental tumors. The in vivo effects of an anti-idiotypic MAb (alpha H7) against a radioiodinated, high affinity, low dissociation rate, monoclonal antiplacental alkaline phosphatase antibody (H7) was investigated. Following in vivo injection of the anti-idiotypic MAb, the radioactivity in experimental tumors was found to decrease only 25% while the reduction of corresponding radioactivity in nontumor tissues amounted to 65-85%, compared to the group receiving no anti-idiotypic MAbs. These results indicate that it is possible to partially clear the circulation and nontumor tissues from excess of radiolabeled idiotypic antibody, without significant decrease in specific tumor localization, increasing the tumor/nontumor ratio three- to fourfold. Circulating nontumor targeting radiolabeled antibodies is one of the major limiting factors in radioimmunotherapy today. Injection of anti-idiotypic MAbs could selectively significantly reduce the radiation dose to radio-sensitive tissues, i.e., bone marrow and intestine, thus improving efficiency in radioimmunoscintigraphy and radioimmunotherapy.

  • 46. Ullén, A
    et al.
    Sandström, P
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sundström, B
    Nilsson, B
    Ärlestig, L
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Use of anticytokeratin monoclonal anti-idiotypic antibodies to improve tumor: nontumor ratio in experimental radioimmunolocalization.1995In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 55, no 23 Suppl, p. 5868s-5873sArticle in journal (Refereed)
    Abstract [en]

    A syngeneic, high-affinity, anti-idiotypic monoclonal antibody (MAb; alpha TS1) raised against an anticytokeratin monoclonal antibody (TS1) was evaluated as a second antibody to promote the rapid clearance of radiolabeled TS1 from the blood during experimental radioimmunolocalization. By using a novel biosensor technology (BIAcore), association rate dissociation rate, and affinity constants between the idiotype and the anti-idiotype could be determined. The in vivo results in nude mice carrying HeLa Hep 2 tumors demonstrate the possibility of selectively regulating the amount of the idiotypic 125I-labeled circulating MAb by in vivo injection of this high-affinity, anti-idiotypic antibody. Injection of the anti-idiotype in a molar ratio of 0.75 to the idiotype cleared the blood pool from circulating radiolabeled idiotype within 24 h, with a concomitant rapid excretion of 125I in urine. The total amount of remaining radioactivity in the animals decreased to 15-20% during these 24 h, with the tumors still retaining 60-65% of their initial radioactivity. This approach, using syngeneic primary and secondary MAbs with minimized immunogenicity, significantly improves the tumor:nontumor ratio, thus improving efficiency in experimental radioimmunolocalization and radioimmunotherapy, leaving the endogenous antibody repertoire of the host unaffected.

  • 47. Ullén, Anders
    et al.
    Nilsson, B
    Åhlström Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Makiya, R
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    In vivo and in vitro interactions between idiotypic and antiidiotypic monoclonal antibodies against placental alkaline phosphatase1995In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 183, no 1, p. 155-165Article in journal (Refereed)
    Abstract [en]

    A monoclonal antiidiotypic antibody alpha H7, was generated against a monoclonal antibody H7 with specificity towards placental alkaline phosphatase. The in vitro and in vivo effects of alpha H7 were investigated. The antiidiotypic antibody was found to generate stable complexes with the radiolabeled idiotypic antibody, visualized both in vivo and in vitro, as revealed by PAGE and autoradiography. Using biosensor technology (BIAcore, Pharmacia) the interactions were followed in real time and the association rate, dissociation rate, and affinity constants between the reactants were determined (KA H7/PLAP 6.7 x 10(9) M-1, KA H7/alpha H7 3.2 x 10(9) M-1). By in vivo injection of the antiidiotype, a rapid dose dependent clearance of circulating radiolabeled idiotypes was demonstrated and a decrease in total body radioactivity was recorded with a concomitant dramatic increase in non-protein-bound 125I excreted in the urine. It is concluded that idiotypic-antiidiotypic interactions offer advantages in the regulation of antibody levels in vivo.

  • 48. Ullén, Anders
    et al.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Nilsson, B
    Ärlestig, L
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Secondary antibodies as tools to improve tumor to non tumor ratio at radioimmunolocalisation and radioimmunotherapy.1996In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 35, no 3, p. 281-285Article in journal (Refereed)
    Abstract [en]

    One way of selectively improving the efficiency of radioimmunolocalization and radioimmunotherapy is to eliminate redundant, circulating, non-targeting radiolabeled antibodies after saturation of the target sites. Secondary antibodies of different types have been proposed as clearing agents for such purposes. The conceptually different approaches of the 'secondary antibody' strategy including its advantages and limitations are discussed. This mini-review also presents a model describing the kinetics of the components (the antigen, the primary and secondary antibodies) and approaches required to improve the efficacy of both radioimmunolocalization and radioimmunotherapy.

  • 49. Ullén, Anders
    et al.
    Sandström, Per
    Rossi Norrlund, Rauni
    Rathsman, Sandra
    Johansson, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Hietala, Sven-Ola
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Stigbrand, Torgny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Dosimetry of fractionated administration of 125I-labeled antibody at experimental radioimmunotargeting.1997In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 80, no 12 Suppl, p. 2510-2518Article in journal (Refereed)
    Abstract [en]

    In this antigen target system, a single injection of a large amount of antibody was found to be more efficient than the same antibody dose subdivided into three or ten fractions. It was concluded that not only the radioactivity but also the amount of antibody per fraction should be considered when determining optimal fractionated radioimmunotherapy.

1 - 49 of 49
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