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Research Articles: Therapeutics, Targets, and Development

Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts

¹ Division of Urology, The University of Florida, Jacksonville, Florida; ² Department of Pharmacology, The University of Florida, Gainesville, Florida; ³ Department of Urology, Nara Medical University, Nara, Japan; and ⁴ Genta Incorporated, Berkeley Heights, New Jersey

Requests for reprints: Charles J. Rosser, Department of Urology, College of Medicine, University of Florida, Suite N2-3, P.O. Box 100247, Gainesville, FL 3210. Phone: 352-392-4504; Fax: 352-392-8846. E-mail: charles.rosser{at}urology.ufl.edu.

Abstract

Expression of the proto-oncogene Bcl-2 is associated with tumor progression. Bcl-2's broad expression in tumors, coupled with its role in resistance to chemotherapy and radiation therapy–induced apoptosis, makes it a rational target for anticancer therapy. Antisense Bcl-2 oligodeoxynucleotide (ODN) reagents have been shown to be effective in reducing Bcl-2 expression in a number of systems. We investigated whether treating human prostate cancer cells with antisense Bcl-2 ODN (G3139, oblimersen sodium, Genasense) before irradiation would render them more susceptible to radiation effects. Two prostate cancer cell lines expressing Bcl-2 at different levels (PC-3-Bcl-2 and PC-3-Neo) were subjected to antisense Bcl-2 ODN, reverse control (CTL), or mock treatment. Antisense Bcl-2 ODN alone produced no cytotoxic effects and was associated with G₁ cell cycle arrest. The combination of antisense Bcl-2 ODN with irradiation sensitized both cell lines to the killing effects of radiation. Both PC-3-Bcl-2 and PC-3-Neo xenografts in mice treated with the combination of antisense Bcl-2 ODN and irradiation were more than three times smaller by volume compared with xenografts in mice treated with reverse CTL alone, antisense Bcl-2 ODN alone, irradiation alone, or reverse CTL plus radiotherapy (P = 0.0001). Specifically, PC-3-Bcl-2 xenograft tumors treated with antisense Bcl-2 ODN and irradiation had increased rates of apoptosis and decreased rates of angiogenesis and proliferation. PC-3-Neo xenograft tumors had decreased proliferation only. This is the first study which shows that therapy directed at Bcl-2 affects tumor vasculature. Together, these findings warrant further study of this novel combination of Bcl-2 reduction and radiation therapy, as well as Bcl-2 reduction and angiogenic therapy. [Mol Cancer Ther 2007;6(1):101–11]

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Received 6/26/06; revised 10/ 3/06; accepted 11/27/06.

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