The thalidomide analogue, CC-4047, induces apoptosis signaling and growth arrest in childhood acute lymphoblastic leukemia cells in vitro and in vivo.
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.
Shalapour
Shabnam
S
Department of Pediatric Oncology/Hematology, Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany, and University Children's Hospital (UKBB), Basel, Switzerland.
Zelmer
Andrea
A
Pfau
Madlen
M
Moderegger
Eva
E
Costa-Blechschmidt
Cristiane
C
van Landeghem
Frank K H
FK
Taube
Tillmann
T
Fichtner
Iduna
I
Bührer
Christoph
C
Henze
Günter
G
Seeger
Karl
K
Wellmann
Sven
S
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
D013792:Thalidomide; C467566:pomalidomide; D053148:Caspase 3