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Combination Bcl-2 Antisense and Radiation Therapy for Nasopharyngeal Cancer

Kenneth W. Yip^1,4, Joseph D. Mocanu^1,4, P.Y. Billie Au^4,7, Gillian T. Sleep^1,4, Dolly Huang^8,, Pierre Busson⁹, Wen-Chen Yeh^4,7, Ralph Gilbert^2,5, Brian O'Sullivan^3,6, Patrick Gullane^2,5, Carlo Bastianutto^1,4 and Fei-Fei Liu^1,3,4,6

Authors' Affiliations: ¹ Division of Applied Molecular Oncology, Ontario Cancer Institute; Departments of ² Surgical Oncology and ³ Radiation Oncology, Princess Margaret Hospital, University Health Network; Departments of ⁴ Medical Biophysics, ⁵ Surgery, and ⁶ Radiation Oncology, University of Toronto; ⁷ Advanced Medical Discovery Institute, University Health Network, Toronto, Ontario, Canada; ⁸ Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Shatin, Hong Kong; and ⁹ Unité Mixte de Recherche 1698, Institut Gustave Roussy, Villejuif, France

Requests for reprints: Fei-Fei Liu, Department of Radiation Oncology, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2123; Fax: 416-946-4586; E-mail: Fei-Fei.Liu{at}rmp.uhn.on.ca.

Purpose: A wide variety of tumors depend on the dysregulation of Bcl-2 family proteins for survival. The resulting apoptotic block can often provide a mechanism for resistance to anticancer treatments, such as chemotherapy and radiation. This current study evaluates the efficacy of combining systemically delivered Bcl-2 phosphorothioate antisense (Bcl-2 ASO) and radiation for nasopharyngeal cancer therapy.

Results: Antisense uptake was unaffected by 0, 3, or 6 Gy radiation. Radiation decreased the fraction of viable C666-1 cells to 60%, with a further decrease to 40% in combination with Bcl-2 ASO. Despite a modest in vitro effect, Bcl-2 ASO alone caused the regression of established xenograft tumors in mice, extending survival by 15 days in a C666-1 and by 6 days in a C15 model. The survival times for mice treated with both Bcl-2 ASO and radiation increased by 52 days in C666-1 and by 20 days in C15 tumors. This combination resulted in a more-than-additive effect in C666-1 tumors. Less impressive gains observed in C15 tumors might be attributable to higher expression of antiapoptotic Bcl-2 family proteins and limited drug distribution in the tumor. Retreatment of C666-1 tumors with the Bcl-2 ASO-radiation combination, however, was effective, resulting in mice surviving for >80 days relative to untreated controls.

Conclusions: Our results show that the Bcl-2 ASO and radiation combination is a highly potent therapy for nasopharyngeal cancer. Further examination of combination therapy with radiation and other Bcl-2 family–targeted anticancer agents in both preclinical and clinical settings is definitely warranted.

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