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 (AdMnSOD) 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 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)(*-) in combination with AdMnSOD plus BCNU may represent a powerful new antitumor regimen against breast cancer.
Sun
Wenqing
W
Free Radical and Radiation Biology Program, Department of Radiation Oncology, and Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa, and VA Medical Center, Iowa City, IA 52242, USA.
Kalen
Amanda L
AL
Smith
Brian J
BJ
Cullen
Joseph J
JJ
Oberley
Larry W
LW
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D002330:Carmustine / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D011839:Radiation, Ionizing; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000970:Antineoplastic Agents; D013481:Superoxides; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D005978:Glutathione; D002330:Carmustine; D019803:Glutathione Disulfide