Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP155) Proteasome inhibitor Bortezomib enhances effectiveness of radioimmunotherapy of diffuse large B-cell lymphoma.

Pervan, Milena*,1, de Vos, Sven 2, Calimlim, Jeffrey2, Said, Jonathan2, McBride, William1, 1 Radiation Oncology Department, Los Angeles, CA2 Hem/Onc Department, Los Angeles, CA

ABSTRACT- The prognosis is poor for patients with relapsed or refractory diffuse large B-cell lymphomas (DLBCL) following chemotherapy. Novel therapies using monoclonal antibody against CD20, either in an unmodified form (Rituximab) or radiolabeled with Ytrium-90 (Zevalin), have shown improved overall response, but complete response rates are still below 45%. We have previously shown the proteasome inhibitor Bortezomib to radiosensitize cancer cells to irradiation and undertook this study to evaluate whether combining it with Rituximab or Zevalin would have improved efficacy over either treatment alone. In vitro, Bortezomib (0.5-3nM) and Rituximab (0.1-0.5g/ml) had additive anti-proliferative effects on the DLBCL cell line SUDHL-16, as assessed by MTT assay. Caspase 3 activation, measured by PARP cleavage, was increased 3hrs following combined Bortezomib and Rituximab treatment and apoptosis was confirmed by TUNEL and Annexin V staining. Bortezomib treatment did not alter CD20 expression levels of SUDHL-16 cells. The treatments were then evaluated in vivo. SUDHL-16 tumors were established in the hind legs of SCID-Beige mice. When tumors were 6mm in diameter, mice received i.v. injections of Rituximab at a dose of 1 mg/mouse alone or in combination with Bortezomib at 0.01 mg/mouse, which was given three hours prior to the first treatment and twice per week thereafter. All treatment schedules delayed tumor growth compared with controls. After 2 weeks of treatment, Bortezomib alone reduced tumor progression by 38%, Rituximab by 71%, and the combined treatment by 88%. Combination of Bortezomib with Zevalin (30 Ci/ mouse) in the same SUDHL-16 SCID model was also more active than any single agent treatment. Morphological and molecular analysis of treated tumors is underway. Our studies suggest that combining Bortezomib with Rituximab or Zevalin can be beneficial for the treatment of DLBCL.

Key words: Bortezomib, Rituximab, Zevalin, DLBCL

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2005 RRS