title: Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts.
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.
authors.affiliation: Department of Urology, College of Medicine, University of Florida, Suite N2-3, P.O. Box 100247, Gainesville, FL, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Anai
authors.forename: Steve
authors.initials: S
authors.lastname: Goodison
authors.forename: Kathleen
authors.initials: K
authors.lastname: Shiverick
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirao
authors.forename: Bob D
authors.initials: BD
authors.lastname: Brown
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Rosser
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000532:radiotherapy; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000532:radiotherapy*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency* / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D042442:Vascular Endothelial Growth Factors