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Bcl-2 Antisense Oligonucleotides Are Effective against Systemic but not Central Nervous System Disease in Severe Combined Immunodeficient Mice Bearing Human t(14;18) Follicular Lymphoma¹

Division of Hematology and Oncology, Departments of Medicine [R. M., Y. A., N. H., A. A-K.], Pathology [M. D., A. M.], and Chemistry [A. A., C. C.], Wayne State University, Karmanos Cancer Institute, Detroit, Michigan 48201

The t(14;18) is present in 85–90% of follicular lymphomas. It results in overexpression of the Bcl-2 protein, which inhibits apoptosis and plays a role in lymphomagenesis. Bcl-2 antisense oligonucleotides (ODNs) down-regulate Bcl-2 expression and inhibit growth of the follicular lymphoma cell line WSU-FSCCL. In this study, we have established a human lymphoma xenograft model in severe combined immunodeficient (SCID) mice using the WSU-FSCCL cell line. s.c., i.v., or i.p. injection of WSU-FSCCL cells into SCID mice results in the development of disseminated tumors, with the liver, spleen, bone marrow, and lymph nodes as major sites of disease. Tumors were fatal in 7–14 weeks, depending on cell inoculum and route of administration. Immunohistochemistry, flow cytometry, and cytogenetic analysis confirmed the human B-cell origin of tumor cells in the xenograft. Phosphorothioate ODNs against the translation initiation site of bcl-2 mRNA in the antisense and mismatched antisense sequences were administered i.v. or i.p. to the xenograft models three times a week for 2 weeks, starting on day 7 after tumor injections. Antisense-treated animals had significantly longer survival (mean, 11.6 weeks) compared with 7.6 weeks for the control group and 7.5 weeks for the mismatched antisense-treated animals (P = 0.002 and 0.004, respectively). More significantly, a pathological examination showed no tumor in the liver, spleen, or bone marrow of the antisense group. However, subsequent experiments showed that the central nervous system was involved, causing mice to die although other sites were disease free. We conclude that bcl-2 antisense ODN therapy is effective against systemic FSCCL disease in SCID mice xenografts; however, it does not prevent disease dissemination into the central nervous system causing animal death.