Enhancing the Antitumor Activity of Adriamycin and Ionizing 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 (O-2(center dot-)) to hydrogen peroxide (H2O2), combined with inhibiting the removal of H2O2, further increases H2O2 levels, leading to increased cytotoxicity. We hypothesized that increasing endogenous O-2(center dot-) 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 O-2(center dot-), 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 O-2(center dot-) in combination with AdMnSOD plus BCNU may represent a powerful new antitumor regimen against breast cancer. [Cancer Res 2009;69(10):4294-300]