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A novel alkylating ...
A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells
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- Ray, Arghya (författare)
- Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA.
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- Ravillah, Durgadevi (författare)
- Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA.
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- Das, Deepika S. (författare)
- Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA.
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- Song, Yan (författare)
- Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA.
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- Nordström, Eva (författare)
- Karolinska Inst, Oncopeptides AB, Sci Pk, Solna, Sweden.
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- Gullbo, Joachim (författare)
- Uppsala universitet,Experimentell och klinisk onkologi
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- Richardson, Paul G. (författare)
- Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA.
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- Chauhan, Dharminder (författare)
- Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA.
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- Anderson, Kenneth C. (författare)
- Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA.;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA.
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Harvard Med Sch, Dept Med Oncol, LeBow Inst Myeloma Therapeut, Dana Farber Canc Inst, Boston, MA USA;Harvard Med Sch, Jerome Lipper Myeloma Ctr, Dana Farber Canc Inst, Boston, MA USA. Karolinska Inst, Oncopeptides AB, Sci Pk, Solna, Sweden. (creator_code:org_t)
- 2016-04-20
- 2016
- Engelska.
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 174:3, s. 397-409
- Relaterad länk:
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https://onlinelibrar...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Our prior study utilized both invitro and invivo multiple myeloma (MM) xenograft models to show that a novel alkylator melphalan-flufenamide (Melflufen) is a more potent anti-MM agent than melphalan and overcomes conventional drug resistance. Here we examined whether this potent anti-MM activity of melflufen versus melphalan is due to their differential effect on DNA damage and repair signalling pathways via -H2AX/ATR/CHK1/Ku80. Melflufen-induced apoptosis was associated with dose- and time-dependent rapid phosphorylation of -H2AX. Melflufen induces -H2AX, ATR, and CHK1 as early as after 2h exposure in both melphalan-sensitive and -resistant cells. However, melphalan induces -H2AX in melphalan-sensitive cells at 6h and 24h; no -H2AX induction was observed in melphalan-resistant cells even after 24h exposure. Similar kinetics was observed for ATR and CHK1 in meflufen- versus melphalan-treated cells. DNA repair is linked to melphalan-resistance; and importantly, we found that melphalan, but not melflufen, upregulates Ku80 that repairs DNA double-strand breaks. Washout experiments showed that a brief (2h) exposure of MM cells to melflufen is sufficient to initiate an irreversible DNA damage and cytotoxicity. Our data therefore suggest that melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in MM cells.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Nyckelord
- Myeloma
- apoptosis
- novel therapeutics
- alkylating agents
- melflufen
- melphalan
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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