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In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, 6341-6352 p.Article in journal (Refereed) Published
Abstract [en]

The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34(+) progenitor cells and a more differentiated CD34(+) derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.

Place, publisher, year, edition, pages
2017. Vol. 8, no 4, 6341-6352 p.
Keyword [en]
melflufen, drug development, alkylator, pre-clinical, acute myeloid leukemia
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-317697DOI: 10.18632/oncotarget.13856ISI: 000393289000079PubMedID: 27974676OAI: oai:DiVA.org:uu-317697DiVA: diva2:1082669
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2017-03-17Bibliographically approved

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Strese, SaraHassan, Saadia BashirHaglund, CarolineHöglund, MartinLarsson, RolfGullbo, Joachim
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Cancer Pharmacology and Computational MedicineDepartment of Immunology, Genetics and PathologyHaematologyExperimental and Clinical Oncology
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