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The Thalidomide Analogue, CC-4047, Induces Apoptosis Signaling and Growth Arrest in Childhood Acute Lymphoblastic Leukemia Cells In vitro and In vivo

Authors' Affiliations: ¹ Department of Pediatric Oncology/Hematology, ² Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum; ³ Department of Experimental Pharmacology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany; and ⁴ University Children's Hospital (UKBB), Basel, Switzerland

Requests for reprints: Sven Wellmann, University Children's Hospital (UKBB), CH-4005 Basel, Switzerland. Phone: 41-61-685-6750; Fax: 41-61-685-6012; E-mail: sven.wellmann{at}ukbb.ch.

Purpose: 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).

Experimental Design: 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.