title: The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro.
abstract: OBJECTIVE
  The dipeptide J1 acts as a prodrug of melphalan with a significant increased potency in vitro resulting from activation by cellular aminopeptidases. The current study was performed to evaluate the ex vivo profile of J1 using 176 primary tumor cell cultures from patients. In addition, the activity of J1 in combination with eight standard drugs, representing different mechanistic classes, was studied in nine different human tumor cell lines of different histopathological origin.
  
  
  METHODS
  Ex vivo evaluation of tumor type selectivity, was performed using the established fluorometric microculture cytotoxicity assay (FMCA). Combinations between J1 and eight standard chemotherapeutic drugs were analyzed using the median-effect method.
  
  
  RESULTS
  The prodrug J1 expressed approximately 50- to 100-fold higher potency but similar activity profile as that of its metabolite, melphalan. The difference was greater in some diagnoses (e.g. breast cancer, NHL and AML), and exceptionally high in some breast cancer samples with aggressive phenotypes. Combination analysis of J1 and standard chemotherapeutics yielded several potentially additive and synergistic interactions, most striking for etoposide with significant synergism in all studied cell lines.
  
  
  CONCLUSIONS
  In conclusion, the ex vivo profile suggests that further evaluation of J1 as the alkylating agent in for example aggressive breast cancer might be of particular interest, preferentially in combination with DNA-topoisomerase II inhibitors like etoposide.
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University Hospital, Entrance 61, 4th floor, 75185 Uppsala, Sweden. Malin.Wickstrom@medsci.uu.se
authors.forename: Malin
authors.initials: M
authors.lastname: Wickström
authors.forename: Caroline
authors.initials: C
authors.lastname: Haglund
authors.forename: Henrik
authors.initials: H
authors.lastname: Lindman
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005470:Fluorometry; D006801:Humans; D008558:Melphalan / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000494:pharmacology
chemical_list: D004151:Dipeptides; C482580:L-melphalanyl-p-L-fluorophenylalanine ethyl ester; D011355:Prodrugs; D008558:Melphalan