Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts.
Monoclonal anti-CD20 antibody (rituximab) is active, but not curative, therapy for B-cell non-Hodgkin's lymphoma. BCL-2 is an antiapoptotic protein whose expression is dysregulated in most indolent B-cell malignancies. Antisense oligonucleotides (AS-ODNs) that down-regulate BCL-2 expression induce apoptosis and chemosensitize B-cell lymphoma cells. We hypothesized that BCL-2 down-regulation by AS-ODNs would sensitize cells to rituximab and improve therapeutic results. There is enhanced apoptosis and reduction in cell numbers when DoHH2 cells are treated in vitro with rituximab plus BCL-2 AS-ODNs, compared with either agent alone. There is little in vitro effect on WSU-FSCCL cells by rituximab, AS-ODNs that down-regulate BCL-2 by targeting the immunoglobulin portions of the BCL-2-immunoglobulin fusion molecule, or a combination of the two. The combination is more effective than either agent alone in clearing DoHH2 cells from ascites in scid mice. Combination therapy with AS-BCL-2-ODNs and rituximab significantly prolongs survival in both the DoHH2 and WSU-FSCCL models. With higher and repeated doses, this combination could be curative. We conclude that the combination of rituximab and antisense-mediated down-regulation of BCL-2 has enhanced activity against human lymphoma, prolongs survival, and could cure mice bearing human lymphoma. This merits investigation in clinical trials.
Smith
Mitchell R
MR
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. m_smith@fccc.edu
Jin
Fang
F
Joshi
Indira
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D003131:Combined Modality Therapy; D015536:Down-Regulation; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008224:Lymphoma, Follicular / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000627:therapeutic use*; D000069283:Rituximab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D000069283:Rituximab