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Targeting aggressiv...
Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide
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- Byrgazov, Konstantin (author)
- Oncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.;St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
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- Andersson, Claes (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Salzer, Benjamin (author)
- St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
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- Bozsaky, Eva (author)
- St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
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- Larsson, Rolf (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Gullbo, Joachim (author)
- Oncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.
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- Lehner, Manfred (author)
- St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
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- Lehmann, Fredrik (author)
- Oncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.
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- Slipicevic, Ana (author)
- Oncopeptides AB, Luntmakragatan 46, SE-11137 Stockholm, Sweden.
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- Kager, Leo (author)
- Med Univ Vienna, St Anna Childrens Hosp, Dept Pediat, Vienna, Austria.;CCRI, Vienna, Austria.
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- Fryknäs, Mårten (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Taschner-Mandl, Sabine (author)
- St Anna Childrens Canc Res Inst CCRI, Vienna, Austria.
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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)
- 2020-07-29
- 2020
- English.
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In: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. - : SAGE PUBLICATIONS LTD. - 1758-8340 .- 1758-8359. ; 12
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Abstract
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- aminopeptidase
- chemotherapy
- melflufen
- metastasis
- osteosarcoma
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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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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show more...
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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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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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THERAPEUTIC ADVA ...
- By the university
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Uppsala University