title: In vitro and in vivo activity of melflufen (J1)in lymphoma.
abstract: BACKGROUND
  Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma.
  
  
  METHODS
  Cytotoxicity of melflufen was assayed in lymphoma cell lines and in primary tumor cells with the Fluorometric Microculture Cytotoxicity Assay and cell cycle analyses was performed in two of the cell lines. Melflufen was also investigated in a xenograft model with subcutaneous lymphoma cells inoculated in mice.
  
  
  RESULTS
  Melflufen showed activity with cytotoxic IC50-values in the submicromolar range (0.011-0.92 μM) in the cell lines, corresponding to a mean of 49-fold superiority (p < 0.001) in potency vs. melphalan. In the primary cultures melflufen yielded slightly lower IC50-values (2.7 nM to 0.55 μM) and an increased ratio vs. melphalan (range 13-455, average 108, p < 0.001). Treated cell lines exhibited a clear accumulation in the G2/M-phase of the cell cycle. Melflufen also showed significant activity and no, or minimal side effects in the xenografted animals.
  
  
  CONCLUSIONS
  This study confirms previous reports of a targeting related potency superiority of melflufen compared to that of melphalan. Melflufen was active in cell lines and primary cultures of lymphoma cells, as well as in a xenograft model in mice and appears to be a candidate for further evaluation in the treatment of this group of malignant diseases.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Maryam
authors.initials: M
authors.lastname: Delforoush
authors.affiliation: Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Strese
authors.affiliation: Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden.|Department of Women's and Children's Health, Karolinska Institutet, Childhood Cancer Research Unit, Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Wickström
authors.affiliation: Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Enblad
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden. Joachim.Gullbo@medsci.uu.se.|Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden. Joachim.Gullbo@medsci.uu.se.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D010649:Phenylalanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D023041:Xenograft Model Antitumor Assays
chemical_list: C585069:melflufen; D010649:Phenylalanine; D008558:Melphalan
keywords: Alkylating agents; Cancer therapeutics; J1; Melflufen; Prodrug