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