Yann Duchartre, Stefanie Bachl, Hye Na Kim, Eun Ji Gang, Solah Lee, Hsiao-chuan Liu, Kirk Shung, Ruth Xu, Aaron Kruse, George Tachas, Halvard-Björn Bönig, Yong-mi Kim
- We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including ß1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin ß1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into “clinical” benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve.
MetadatenAuthor: | Yann Duchartre, Stefanie Bachl, Hye Na Kim, Eun Ji Gang, Solah Lee, Hsiao-chuan Liu, Kirk Shung, Ruth Xu, Aaron Kruse, George Tachas, Halvard-Björn BönigORCiDGND, Yong-mi Kim |
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URN: | urn:nbn:de:hebis:30:3-438125 |
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DOI: | https://doi.org/10.1371/journal.pone.0187684 |
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ISSN: | 1932-6203 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/29117236 |
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Parent Title (English): | PLoS one |
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Publisher: | PLoS |
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Place of publication: | Lawrence, Kan. |
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Contributor(s): | Marina Konopleva |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2017 |
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Date of first Publication: | 2017/11/08 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2017/11/23 |
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Tag: | Acute lymphoblastic leukemia; Cancer chemotherapy; Cancer treatment; Flow cytometry; Integrins; Leukemias; Mouse models; Multiple sclerosis |
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Volume: | 12 |
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Issue: | (11): e0187684 |
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Page Number: | 13 |
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First Page: | 1 |
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Last Page: | 13 |
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Note: | Copyright: © 2017 Duchartre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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HeBIS-PPN: | 424728362 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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