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Targeting aggressiv...
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Byrgazov, KonstantinOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.;St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
(author)
Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide
- Article/chapterEnglish2020
Publisher, publication year, extent ...
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2020-07-29
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SAGE PUBLICATIONS LTD,2020
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-421048
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-421048URI
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https://doi.org/10.1177/1758835920937891DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Background: Low survival rates in metastatic high-grade osteosarcoma (HGOS) have remained stagnant for the last three decades. This study aims to investigate the role of aminopeptidase N (ANPEP) in HGOS progression and its targeting with a novel lipophilic peptidase-enhanced cytotoxic compound melphalan flufenamide (melflufen) in HGOS. Methods: Meta-analysis of publicly available gene expression datasets was performed to determine the impact ofANPEPgene expression on metastasis-free survival of HGOS patients. The efficacy of standard-of-care anti-neoplastic drugs and a lipophilic peptidase-enhanced cytotoxic conjugate melflufen was investigated in patient-derived HGOSex vivomodels and cell lines. The kinetics of apoptosis and necrosis induced by melflufen and doxorubicin were compared. Anti-neoplastic effects of melflufen were investigatedin vivo. Results: ElevatedANPEPexpression in diagnostic biopsies of HGOS patients was found to significantly reduce metastasis-free survival. In drug sensitivity assays, melflufen has shown an anti-proliferative effect in HGOSex vivosamples and cell lines, including those resistant to methotrexate, etoposide, doxorubicin, and PARP inhibitors. Further, HGOS cells treated with melflufen displayed a rapid induction of apoptosis and this sensitivity correlated with high expression ofANPEP. In combination treatments, melflufen demonstrated synergy with doxorubicin in killing HGOS cells. Finally, Melflufen displayed anti-tumor growth and anti-metastatic effectsin vivo. Conclusion: This study may pave the way for use of melflufen as an adjuvant to doxorubicin in improving the therapeutic efficacy for the treatment of metastatic HGOS.
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Andersson, ClaesUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)cland109
(author)
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Salzer, BenjaminSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
(author)
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Bozsaky, EvaSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
(author)
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Larsson, RolfUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)rolflars
(author)
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Gullbo, JoachimOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.
(author)
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Lehner, ManfredSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
(author)
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Lehmann, FredrikOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.
(author)
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Slipicevic, AnaOncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.
(author)
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Kager, LeoMed Univ Vienna, St Anna Childrens Hosp, Dept Pediat, Vienna, Austria.;CCRI, Vienna, Austria.
(author)
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Fryknäs, MårtenUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)mafry516
(author)
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Taschner-Mandl, SabineSt Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
(author)
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Oncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.;St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.Cancerfarmakologi och beräkningsmedicin
(creator_code:org_t)
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In:THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY: SAGE PUBLICATIONS LTD121758-83401758-8359
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Byrgazov, Konsta ...
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Andersson, Claes
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Salzer, Benjamin
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Bozsaky, Eva
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Larsson, Rolf
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Gullbo, Joachim
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Lehner, Manfred
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Lehmann, Fredrik
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Slipicevic, Ana
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Kager, Leo
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Fryknäs, Mårten
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Taschner-Mandl, ...
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THERAPEUTIC ADVA ...
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Uppsala University