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

• Published in: Clinical cancer research Vol. 12; no. 18; pp. 5526 - 5532
• Main Authors: SHALAPOUR, Shabnam, ZELMER, Andrea, SEEGER, Karl, WELLMANN, Sven, PFAU, Madlen, MODEREGGER, Eva, COSTA-BLECHSCHMIDT, Cristiane, VAN LANDEGHEM, Frank K. H, TAUBE, Tillmann, FICHTNER, Iduna, BÜHRER, Christoph, HENZE, Gunter
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2006
• Subjects: ALL; Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Blood Vessels - drug effects; Caspase 3 - metabolism; CC-4047; Cell Proliferation - drug effects; Child, Preschool; childhood; Female; Hematologic and hematopoietic diseases; Humans; Infant; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Transplantation - pathology; Neovascularization, Pathologic - drug therapy; Pharmacology. Drug treatments; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; stroma; Stromal Cells - drug effects; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Thalidomide - therapeutic use; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Human; Antineoplastic agent; Growth; Acute; Malignant hemopathy; In vitro; In vivo; Signal transduction; Cell death; Lymphoproliferative syndrome; Analog; Acute lymphocytic leukemia; Child; Thalidomide; Apoptosis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0719

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 .