2-Methoxyestradiol enhances reactive oxygen species formation and increases the efficacy of oxygen radical generating tumor treatment.
In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.
Lambert
C
C
Institute of Biological Chemistry and Nutrition, University of Hohenheim, Stuttgart, Germany.
Thews
O
O
Biesalski
H K
HK
Vaupel
P
P
Kelleher
D K
DK
Frank
Juergen
J
D000077584:2-Methoxyestradiol; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018496:Hyperoxia; D006979:Hyperthermia, Induced; D019271:Hypoxanthine / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014407:Tumor Cells, Cultured; D014969:Xanthine Oxidase / Q000627:therapeutic use
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D019271:Hypoxanthine; D004958:Estradiol; D000077584:2-Methoxyestradiol; D014969:Xanthine Oxidase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases