| 1. |
- Mårtensson, Linda, et al.
(författare)
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High-Dose Radioimmunotherapy Combined With Extracorporeal Depletion in a Syngeneic Rat Tumor Model
- 2010
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 116:4, s. 1043-1052
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of the current study was to investigate the possibility of increasing the maximal tolerated dose (MTD) of a tumor-selective radiolabeled antibody when radioimmunotherapy (RIT) is combined with extracorporeal depletion of radioimmunoconjugates from the circulation. Furthermore, the authors evaluated whether this increase in dose improved the therapeutic effect on solid manifest tumors in an immunocompetent animal model. METHODS: Rats were injected with high activities/body weight of lutetium (Lu-177)- or yttrium (Y-90)-labeled antibody conjugates (monoclonal antibody tetraazacyclododecanetetraacetic acid-biotin) and subjected to removal of the conjugate from the circulation by extracorporeal affinity adsorption treatment 24 hours postinjection. Myelotoxicity was assessed by analysis of blood parameters for 12 weeks. The effect of increased doses in combination with extracorporeal affinity adsorption treatment was evaluated with respect to myelotoxicity and therapeutic effect in a syngeneic rat colon cancer model. RESULTS: The MTD of Lu-177- or Y-90-labeled immunoconjugates could be increased 2.0x or 1.5x, respectively, when RIT was combined with extracorporeal affinity adsorption treatment. All animals treated with Lu-177- or Y-90-labeled antibodies showed persistent complete response of manifest tumors (approximately 10 x 15 mm) within 16 days postinjection. However, several animals showed disseminated disease 1.5 to 3 months postinjection. CONCLUSIONS: Extracorporeal affinity adsorption treatment is a method that safely and efficiently reduces myelotoxicity associated with RIT. Extracorporeal affinity adsorption treatment allows increased administered activity without increased toxicity, with the aim of increasing the absorbed dose to the tumor. However, because tumor/normal tissue radiosensitivity ratios are more favorable in rodents, it is not possible to draw any conclusions concerning the therapeutic efficacy of increased administered activity in combination with extracorporeal affinity adsorption treatment in this study. Targeted RIT with beta-emitting radionuclides seems not to be effective in microscopic disease, because metastases developed at sites without previously known disease. (C) 2010 American Cancer Society.
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| 2. |
- Nilsson, Rune, et al.
(författare)
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Different toxicity profiles for drug-versus radionuclide-conjugated BR96 monoclonal antibodies in a syngeneic rat colon carcinoma model
- 2011
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Ingår i: Acta Oncologica. - 1651-226X. ; 50:5, s. 711-718
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Tidskriftsartikel (refereegranskat)abstract
- Background. One of many approaches being evaluated in experimental models and in the clinic for the treatment of cancer is the use of antibodies conjugated to various drugs or radionuclides. The aim of the present study was to compare the toxicity profiles of radioimmunoconjugates and drug-immunoconjugates based on the same monoclonal antibody, evaluated in the same experimental model, that much resembles human studies. The pattern of dose-limiting toxicity of a monomethylauristatinconjugated monoclonal antibody (BR96) was compared to that of the same antibody conjugated with lutetium-177, and to the same non-conjugated antibody. Material and methods. Rats with established colon carcinoma were injected with monomethylauristatin-conjugated mAb-BR96, 177 Lu-BR96, or non-conjugated BR96. Liver, kidney, and myelotoxicity were assessed for 100 days by analysis of blood parameters. Body weight and therapeutic effects was also monitored. Results. Myelotoxicity was found to be dose limiting for the radionuclide BR96 conjugate. The dose-limiting factor was prolonged suppression of leukocytes (> 28 days) with increased risk of infections. For monomethylauristatin-conjugated BR96, liver toxicity was dose limiting, whereas no dose-limiting toxicity was observed with non-conjugated BR96. Both the drug-immunoconjugate and the radioimmunoconjugate resulted in decreased platelet counts, but the time to nadir and duration differed. Conclusion. The two conjugates resulted in different patterns of toxicity. By using the two conjugates of BR96 in a sequential therapeutic design it could be possible to increase the therapeutic window and hence probably the efficacy without significantly increasing the toxicity. This concept is regarded as valid regardless of conjugate or model chosen.
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| 3. |
- Nittby, Henrietta, et al.
(författare)
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Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Coping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infections and increases their risk of developing cancer. New technologies to induce antigen selective long-lasting immunosuppression or immune tolerance are therefore much needed.
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| 4. |
- Xue, Zhongtian, et al.
(författare)
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An epigenetic mechanism for high, synergistic expression of indoleamine 2,3-dioxygenase 1 (IDO1) by combined treatment with zebularine and IFN-γ: Potential therapeutic use in autoimmune diseases.
- 2012
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Ingår i: Molecular Immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 51:2, s. 101-111
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Tidskriftsartikel (refereegranskat)abstract
- IDO1 can be induced by interferon gamma (IFN-γ) in multiple cell types. We have earlier described that the DNA methyltransferase inhibitor zebularine also induces IDO1 in several rat cell clones. We now describe a synergistic induction of IDO1 expression by IFN-γ and zebularine. To elucidate the mechanism of the IDO1 induction we have studied the methylation status in the promoter region of the IDO1 gene from both human monocytic THP-1 cells and H1D2 rat colon cancer cells. Interestingly, the IDO1 promoter is hypermethylated and IFN-γ is shown to induce a significant demethylation. The synergism in effect of zebularine and IFN-γ on IDO1 expression is paralleled by a similar synergistic effect on expression of two other IFN-γ-responsive genes, the transcription factors STAT1 and IRF1 with binding sites in the IDO1 promoter region. The demonstrated synergistic activation of IDO1 expression has implications in relation to therapeutic induction of immunosuppression in autoimmunity and chronic inflammation.
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