title: The thalidomide analogue, CC-4047, induces apoptosis signaling and growth arrest in childhood acute lymphoblastic leukemia cells in vitro and in vivo.
abstract: OBJECTIVE
  Thalidomide and its analogues have shown promise in the treatment of multiple myeloma but their therapeutic potential has not been evaluated in models of acute lymphoblastic leukemia (ALL).
  
  
  METHODS
  We assessed the effects of the thalidomide analogue, CC-4047, on the growth and apoptosis signaling of human B cell precursor (BCP) ALL cell lines and freshly obtained childhood BCP-ALL cells grown with or without stromal cells. In addition, we studied the effects of CC-4047 on the progression and dissemination of xenotransplanted human BCP-ALL cells in nonobese diabetic/severe combined immunodeficiency mice.
  
  
  RESULTS
  CC-4047 reduced the proliferation of human BCP-ALL cell lines in vitro. In contrast with the antileukemic effect of cytarabin, this was more pronounced when cell lines or freshly obtained childhood BCP-ALL cells were cocultured with stromal cells. CC-4047 induced the cleavage of caspase-3, caspase-9, and poly(ADP-ribose) polymerase in stroma-cocultured BCP-ALL cells. The inhibition of tumor growth, caspase-3 cleavage, and reduced microvessel density was observed in nonobese diabetic/severe combined immunodeficiency mice inoculated s.c. with childhood BCP-ALL cells upon CC-4047 treatment. After i.v. BCP-ALL xenotransplantation, CC-4047 reduced splenic dissemination.
  
  
  CONCLUSIONS
  The thalidomide analogue, CC-4047, displays profound cytostatic effects on stroma-supported human ALL cells both in vitro and in vivo.
authors.affiliation: Department of Pediatric Oncology/Hematology, Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany, and University Children's Hospital (UKBB), Basel, Switzerland.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Shalapour
authors.forename: Andrea
authors.initials: A
authors.lastname: Zelmer
authors.forename: Madlen
authors.initials: M
authors.lastname: Pfau
authors.forename: Eva
authors.initials: E
authors.lastname: Moderegger
authors.forename: Cristiane
authors.initials: C
authors.lastname: Costa-Blechschmidt
authors.forename: Frank K H
authors.initials: FK
authors.lastname: van Landeghem
authors.forename: Tillmann
authors.initials: T
authors.lastname: Taube
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.forename: Christoph
authors.initials: C
authors.lastname: Bührer
authors.forename: Günter
authors.initials: G
authors.lastname: Henze
authors.forename: Karl
authors.initials: K
authors.lastname: Seeger
authors.forename: Sven
authors.initials: S
authors.lastname: Wellmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001808:Blood Vessels / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D017154:Stromal Cells / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D013792:Thalidomide; C467566:pomalidomide; D053148:Caspase 3