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 G(1) 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.
Highlights
Depending on the initial serum prostate-specific antigen level, Gleason score on biopsy, or clinical stage, only 33% to 56% of patients undergoing external beam radiotherapy (XRT) for localized prostate cancer were disease-free 5 years after initial radiation therapy (1 – 6)
We show that antisense Bcl-2 ODN sensitized PC-3-Bcl-2 to irradiation in clonogenic assays, and that antisense Bcl-2 – treated and irradiated xenograft tumors were markedly smaller, had higher rates of apoptosis and decreased proliferation than control tumors
To determine the effects of antisense Bcl-2 ODN on cell proliferation and viability, PC-3-Bcl-2 and PC-3-Neo prostate cancer cell lines were treated for 72 h with antisense Bcl2 ODNs reverse CTL ODN, or mock
Summary
Depending on the initial serum prostate-specific antigen level, Gleason score on biopsy, or clinical stage, only 33% to 56% of patients undergoing external beam radiotherapy (XRT) for localized prostate cancer were disease-free 5 years after initial radiation therapy (1 – 6). Prostate tumors are notoriously resistant to total doses of 75 to 80 Gy. Higher doses are not generally administered because of the increased risk of toxicity and the lack of clinical data supporting improved local tumor control. Because improved local tumor control is a therapeutic goal for most cancers, various strategies for sensitizing tumors to radiation have been tested over the last 20 years (7 – 12). All of these strategies have involved the systemic administration of drugs or other agents that have specific toxicities of their own, which almost always limits pharmacologic doses to levels below what is needed to sensitize tumors. No sensitizing strategies are currently available for widespread use
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