title: Radiosensitization and modulation of p44/42 mitogen-activated protein kinase by 2-Methoxyestradiol in prostate cancer models.
abstract: 2-Methoxyestradiol (2ME2) is an endogenous estradiol metabolite that inhibits microtubule polymerization, tumor growth, and angiogenesis. Because prostate cancer is often treated with radiotherapy, and 2ME2 has shown efficacy as a single agent against human prostate carcinoma, we evaluated 2ME2 as a potential radiosensitizer in prostate cancer models. A dose-dependent decrease in mitogen-activated protein kinase phosphorylation was observed in human PC3 prostate cancer cells treated with 2ME2 for 18 h. This decrease correlated with in vitro radiosensitization measured by clonogenic assays, and these effects were blocked by the expression of constitutively active MEK. Male nude mice with subcutaneous PC3 xenografts in the hind leg were treated with 2ME2 (75 mg/kg) p.o. for 5 days, and 2 Gy radiation fractions were delivered each day at 4 h after drug treatment. A statistically significant super-additive effect between radiation and 2ME2 was observed in this subcutaneous model, using analysis of within-animal slopes. A PC-3M orthotopic model was also used, with bioluminescence imaging as an end point. PC-3M cells stably expressing the luciferase gene were surgically implanted into the prostates of male nude mice. Mice were given oral doses of 2ME2 (75 mg/kg), with radiation fractions (3 Gy) delivered 4 h later. Mice were then imaged weekly for 4 to 5 weeks with a Xenogen system. A significant super-additive effect was also observed in the orthotopic model. These data show that 2ME2 is an effective radiosensitizing agent against human prostate cancer xenografts, and that the mechanism may involve a decrease in mitogen-activated protein kinase phosphorylation by 2ME2.
authors.affiliation: Department of Radiation Oncology, Cancer Center, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: Eli V
authors.initials: EV
authors.lastname: Casarez
authors.forename: Marya E
authors.initials: ME
authors.lastname: Dunlap-Brown
authors.forename: Mark R
authors.initials: MR
authors.lastname: Conaway
authors.forename: George P
authors.initials: GP
authors.lastname: Amorino
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000378:metabolism* / Q000532:radiotherapy*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D040521:Subcutaneous Tissue; D016042:Transplantation, Heterotopic; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays