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Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Request for reprints: Mitchell R. Smith, Lymphoma Service, Fox Chase Cancer Center, Room C307, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-2674; Fax: 215-728-3639. E-mail: m_smith{at}fccc.edu

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.

Key Words: rituximab • apoptosis • non–Hodgkin's lymphoma

Grant support: NIH grant RO1CA71552, Fox Chase Cancer Center Core grant NIH CA06927, and the Mary L. Smith Charitable Lead Trust and the Martha Rogers Charitable Trust grants. Additional support from the Janice Charach Epstein Research Fund and the Lester I. Smith Research Fund.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/14/04; revised 7/24/04; accepted 9/20/04.