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Enhancing the Antitumor Activity of Adriamycin and Ionizing Radiation

¹ Free Radical and Radiation Biology Program, Department of Radiation Oncology, and Holden Comprehensive Cancer Center, ² Department of Biostatistics, College of Public Health, and ³ Department of Surgery, Carver College of Medicine, The University of Iowa, and VA Medical Center, Iowa City, Iowa

Requests for reprints: Joseph J. Cullen, 4605 JCP University of Iowa Hospitals and Clinics, 200 Hawkins Drive, The University of Iowa, Iowa City, IA 52242. Phone: 319-335-8019; Fax: 319-953-6399; E-mail: joseph-cullen{at}uiowa.edu.

Key Words: breast cancer • superoxide dismutase • adenovirus • Adriamycin • radiation

Overexpression of manganese superoxide dismutase (MnSOD), when combined with certain chemicals that inhibit peroxide removal, increases cancer cell cytotoxicity. Elevating MnSOD levels in cells enhances the conversion of superoxide (O₂^–) to hydrogen peroxide (H₂O₂), combined with inhibiting the removal of H₂O₂, further increases H₂O₂ levels, leading to increased cytotoxicity. We hypothesized that increasing endogenous O₂^– production in cells that were pretreated with adenoviral MnSOD (AdMnSOD) plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) would lead to an increased level of intracellular H₂O₂ accumulation and increased cell killing. The cytotoxic effects of Adriamycin or radiation, agents known to produce O₂^–, were determined in MDA-MB-231 breast cancer cells pretreated with AdMnSOD plus BCNU both in vitro and in vivo. In vitro, AdMnSOD plus BCNU sensitized cells to the cytotoxicity of Adriamycin or radiation. In vivo, AdMnSOD, BCNU, and Adriamycin or ionizing radiation inhibited tumor growth and prolonged survival. The results suggest that agents that produce O₂^– in combination with AdMnSOD plus BCNU may represent a powerful new antitumor regimen against breast cancer. [Cancer Res 2009;69(10):4294–300]