Melphalan is a widely used classical chemotherapeutic agent in the group of alkylating agents that was developed more than 50 years ago, and substantial clinical experience has been accumulated. Several APN-directed therapies have been investigated clinically, for example, the inhibitor Ubenimex (bestatin). Different approaches have been used to develop new drugs directed at this target, including enzyme inhibitors and APN-targeted carrier constructs, as reviewed. Together, these abilities suggest APN as a potential therapeutic target in the treatment of cancer. The multiple functions of APN have lead to its designation as a “moonlighting ectoenzyme”. The Zn 2+-dependent membrane-bound ectopeptidase aminopeptidase N (APN, also known as CD13), widely expressed in mammalian cells, plays an important role in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. This review summarizes the current preclinical and clinical knowledge of melflufen.Īn increased expression of various hydrolytic enzymes like peptidases, esterases, and proteases has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes. Furthermore, anti-angiogenic properties of melflufen have been described.Ĭonsequently, it is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target. Received: OctoAccepted: ApPublished: JAbstractĪminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. Keywords: melflufen, aminopeptidase, cancer, targeted chemotherapy Malin Wickström 1,2, Peter Nygren 1,3, Rolf Larsson 1, Johan Harmenberg 4, Jakob Lindberg 4, Per Sjöberg 4, Markus Jerling 4, Fredrik Lehmann 5, Paul Richardson 6, Kenneth Anderson 6, Dharminder Chauhan 6 and Joachim Gullbo 1,3ġ Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, Uppsala SE, SwedenĢ Department of Women’s and Children’s Health, Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Swedenģ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Swedenĥ Recipharm OT Chemistry AB, Uppsala, SwedenĦ Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
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