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The peptidase-potentiated alkylator melflufen demonstrate antileukemic activity in acute myeloid leukemia, in vitro and in vivo
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(English)Manuscript (preprint) (Other academic)
National Category
Clinical Medicine Cancer and Oncology
URN: urn:nbn:se:uu:diva-263130OAI: oai:DiVA.org:uu-263130DiVA: diva2:860858
Available from: 2015-10-14 Created: 2015-09-27 Last updated: 2016-01-13
In thesis
1. Anticancer Activity of Melflufen: Preclinical Studies of a Novel Peptidase-Potentiated Alkylator
Open this publication in new window or tab >>Anticancer Activity of Melflufen: Preclinical Studies of a Novel Peptidase-Potentiated Alkylator
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Melflufen (melphalan flufenamide, chemical name L-melphalanyl-p-L-fluorophenylalanine ethyl ester hydrochloride, previously called J1) is a derivative of the classical alkylating agent melphalan. Melflufen is potentiated by hydrolytic cleavage by aminopeptidase N (APN), leading to high intracellular concentrations of alkylating moieties and subsequent cell death. Increased APN expression is associated with the malignant phenotype of several human cancers, including acute myeloid leukemia, lymphoma and ovarian cancer, and plays a functional role in tumor angiogenesis. Therefore investigations of melflufen activity in these malignancies as well as detailed studies of inhibition of angiogenesis are interesting. The aim of this project was to investigate the cytotoxic and antiangiogenic effect, in vitro and in vivo, of melflufen, compared to melphalan and other cytotoxic drugs used in the clinic.

We showed that melflufen was more effective than its parental drug melphalan in lymphoma, AML and ovarian cancer in cell lines as well as in primary patient samples. An improved in vitro therapeutic index was demonstrated by an increased cytotoxic activity in the patient samples compared to normal peripheral blood mononuclear cells (PBMCs). Furthermore, melflufen in combination with cytarabine was synergistic in an AML cell line in a sequence-dependent manor. Melflufen was shown effective in several animal models using lymphoma, AML and ovarian cell xenografts (single drug or in combination), including an intraperitoneal ovarian xenograft. Finally, we demonstrated that melflufen had antiangiogenic properties in several different models.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 55 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1145
cancertherapy, preclinical studies, melflufen, aminopeptidase-potentiated, cancer, angiogenesis
National Category
Clinical Medicine Cancer and Oncology
Research subject
Clinical Pharmacology
urn:nbn:se:uu:diva-263133 (URN)978-91-554-9371-4 (ISBN)
Public defence
2015-12-12, Enghoffsalen, Akademiska sjukhuset, Ing 50, Uppsala, 09:00 (Swedish)
Available from: 2015-11-19 Created: 2015-09-27 Last updated: 2016-01-13

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