The Combination of the Proteasome Inhibitor Bortezomib and the Bcl-2 Antisense Molecule Oblimersen Sensitizes Human B-Cell Lymphomas to Cyclophosphamide

• DOI: 10.1158/1078-0432.ccr-05-0308
• Publication Date: 2006-05-04T15:45:13Z
• Authors: Owen A. O'Connor; Emily A. Smith; Lorraine E. Toner; Julie Teruya-Feld...; Stanley Frankel; Mark Rolfe; Xiaohui Wei; Shujun Liu; Guido Marcucci; Kenneth K. Chan; Asher Chanan-Khan
• Keywords: 0301 basic medicine; Lymphoma, B-Cell; Cell Survival; Transplantation, Heterologous; Mice, SCID; Oligonucleotides, Antisense; Thionucleotides; Boronic Acids; Genes, bcl-2; 3. Good health; Bortezomib; Kinetics; Mice; 03 medical and health sciences; Cell Line, Tumor; Pyrazines; Animals; Humans; Protease Inhibitors; Cyclophosphamide; Proteasome Inhibitors; Cell Division

Abstract Purpose: To determine whether the combination of proteasome inhibitor bortezomib and bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide. Experimental Design: Cytotoxicity assays were conducted if there was any additive or synergistic interaction between combinations bortezomib, oblimersen, cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments severe combined immunodeficiency beige mice done xenografts which different schedules explored. Bcl-2 levels determined treated tumors, some resected at end experiment evaluated pathologically. Results: The results suggest that seem interact least an fashion, addition this drug markedly improve tumor cell kill. In addition, it seems may be schedule-dependent, with requirement for pretreatment. Animals triplet schedule-dependent manner experienced pathologic complete regression disease, not observed other treatment cohorts. also seemed increase intracellular resulted marked reduction Bcl-2. Histologic studies confirmed necrosis caspase-3 activation only cohort receiving all three drugs. Conclusion: use Bcl-2-directed therapy sensitizes cells cytotoxic drugs like This offer new opportunities integrating novel targeted therapies conventional chemotherapy.