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

Authors' Affiliations: ¹ Department of Medicine, Lymphoma, and Developmental Chemotherapy Service, ² Laboratory of Experimental Therapeutics for Lymphoproliferative Disorders, and ³ Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, ⁴ Roswell Park Cancer Center, Buffalo, New York, ⁵ Genta Pharmaceuticals, Berkeley Heights, New Jersey, ⁶ Millennium Pharmaceuticals, Cambridge, Massachusetts ⁷ Colleges of Pharmacy and Medicine and Public Health, and ⁸ Division of Hematological Oncology, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio

Requests for reprints: Owen A. O'Connor, Division of Hematologic Oncology, Lymphoma and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan Kettering Cancer Center, Box 329, 1275 York Avenue, New York, NY 10021. Phone: 212-639-8889; Fax: 212-639-2767; E-mail: oconnoro{at}mskcc.org.

Purpose: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide.

Experimental Design: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored. Bcl-2 and oblimersen levels were determined in treated tumors, some of which were resected at the end of the in vivo experiment and evaluated pathologically.

Results: The results suggest that the combination of bortezomib and oblimersen seem to interact in at least an additive fashion, and that the addition of cyclophosphamide to this drug combination can markedly improve tumor cell kill. In addition, it seems that these drug combinations may be schedule-dependent, with a requirement for oblimersen pretreatment. Animals treated with the triplet drug combination in a schedule-dependent manner experienced pathologic complete regression of disease, which was not observed in other treatment cohorts. The addition of bortezomib also seemed to increase the levels of intracellular oblimersen, which resulted in a marked reduction in Bcl-2. Histologic studies confirmed marked necrosis and caspase-3 activation only in the cohort receiving all three drugs.

Conclusion: The use of Bcl-2-directed therapy and a proteasome inhibitor sensitizes human lymphoma cells to cytotoxic drugs like cyclophosphamide. This combination may offer new opportunities for integrating novel targeted therapies with conventional chemotherapy.

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