title: Anginex synergizes with radiation therapy to inhibit tumor growth by radiosensitizing endothelial cells.
abstract: We have demonstrated that the designed peptide anginex displays potent antiangiogenic activity. The aim of our study was to investigate the effect of anginex on established tumor vasculature as an adjuvant to radiation therapy of solid tumors. In the MA148 human ovarian carcinoma athymic mouse model, anginex (10 mg/kg) in combination with a suboptimal dose of radiation (5 Gy once weekly for 4 weeks) caused tumors to regress to an impalpable state. In the more aggressive SCK murine mammary carcinoma model, combination of anginex and a single radiation dose of 25 Gy synergistically increased the delay in tumor growth compared to the tumor growth delay caused by either treatment alone. Immunohistochemical analysis also demonstrated significantly enhanced effects of combined treatment on tumor microvessel density and tumor or endothelial cell proliferation and viability. In assessing physiologic effects of anginex, we observed a reduction in tumor perfusion and tumor oxygenation in SCK tumors after 5-7 daily treatments with anginex with no reduction in blood pressure. To test anginex as a radiosensitizer, additional studies using SCK tumors were performed. Three daily i.p. injections of anginex were able to enhance the effect of 2 radiation doses of 10 Gy, resulting in 50% complete responses, whereas the known antiangiogenic agent angiostatin did not enhance the radiation response of SCK tumors. Mechanistically, it appears that anginex functions as an endothelial cell-specific radiosensitizer because anginex showed no effect on in vitro radiosensitivity of SCK or MA148 tumor cells, whereas anginex significantly enhanced the in vitro radiosensitivity of 2 endothelial cell types. This work supports the idea that the combination of the antiangiogenic agent anginex and radiation may lead to improved clinical outcome in treating cancer patients.
authors.affiliation: Department of Biochemistry, University of Minnesota Academic Health Center, Minneapolis, MN 55455, USA.
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.forename: Brent W
authors.initials: BW
authors.lastname: Williams
authors.forename: Chang W
authors.initials: CW
authors.lastname: Song
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D010100:Oxygen / Q000378:metabolism; D010455:Peptides; D011506:Proteins / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D010455:Peptides; D011506:Proteins; D011838:Radiation-Sensitizing Agents; C111993:betapep-25 protein, synthetic; D010100:Oxygen