Abstract
Aminopeptidases 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. 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.Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. 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. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Furthermore, anti-angiogenic properties of melflufen have been described.Consequently, 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. This review summarizes the current preclinical and clinical knowledge of melflufen.
Highlights
An 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 [1]
Aminopeptidases are widely distributed enzymes catalyzing the cleavage of amino acids from the amino terminus of protein or peptide substrates, and may localize as subcellular organelles in cytoplasm or as membrane components
Along with other hydrolytic enzymes, several aminopeptidases have been described as being overexpressed in human malignancies, suggesting their utilization as anti-tumor targets [1]
Summary
An 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 [1]. Immunohistochemistry of tumor sections from melflufen- but not melphalan- or vehicle-treated mice showed increased caspase-3 activation, reduced Ki67 positivity, and decreased mean vascular density, suggesting apoptosis and anti-angiogenic efficacy [21] This low dose was effective in nude rats xenografted with the same cells (SH-SY5Y). A higher, but tolerable, dose (10 μmol/kg) of melflufen was effective in nude rats xenografted with the resistant SK-N-BE(2) cell line, showing significant tumor growth inhibition, apoptosis, and decreased proliferation [21]. The Vk*MYC transgenic mouse with spontaneously occurring myeloma tumors has been suggested as an alternative model to predict single-agent drug activity [39] Melflufen in this model (given as 4 mg/kg i.p. injection twice weekly) was highly effective, showing a Vk*MYC response (defined as > 50% reduction in M-spike at 14 days) in 66% of treated animals, and the average M-spike reduction ranked highest out of 18 investigational anti-multiple myeloma agents examined [39]. While non-hematologic adverse events were infrequent, hematologic toxicity was common, but manageable, with cycle prolongations, dose modifications, and supportive therapy
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