The thalidomide analogue, CC-4047, induces apoptosis signaling and growth arrest in childhood acute lymphoblastic leukemia cells in vitro and in vivo

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Item Type:	Article
Title:	The thalidomide analogue, CC-4047, induces apoptosis signaling and growth arrest in childhood acute lymphoblastic leukemia cells in vitro and in vivo
Creators Name:	Shalapour, S., Zelmer, A., Pfau, M., Moderegger, E., Costa-Blechschmidt, C., van Landeghem, F.K., Taube, T., Fichtner, I., Buehrer, C., Henze, G., Seeger, K. and Wellmann, S.
Abstract:	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.
Keywords:	Apoptosis, Blood Vessels, Caspase 3, Cell Proliferation, Cultured Tumor Cells, Inbred NOD Mice, Neoplasm Transplantation, SCID Mice, Pathologic Neovascularization, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Stromal Cells, Thalidomide, Xenograft Model Antitumor Assays, Animals, Mice
Source:	Clinical Cancer Research
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Volume:	12
Number:	18
Page Range:	5526-5532
Date:	15 September 2006
Official Publication:	https://doi.org/10.1158/1078-0432.CCR-06-0719
PubMed:	View item in PubMed

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