title: Oral administration of an estrogen metabolite-induced potentiation of radiation antitumor effects in presence of wild-type p53 in non-small-cell lung cancer.
abstract: OBJECTIVE
  The purpose of this study was to investigate the efficacy of 2-methoxyestradiol as an antitumor and radiosensitizing agent for the treatment of human malignancy.
  
  
  METHODS
  Two cancer cell lines with wild-type p53 status were exposed first to irradiation and then to an oral formulation of the nontoxic metabolite 2-methoxyestradiol (2ME) to stabilize p53 levels.
  
  
  RESULTS
  Cell growth was inhibited via G1 growth and apoptosis. Subsequent in vitro growth and Tunel assays indicated that this combination was superior to radiation alone at inducing p53 protein accumulation, stabilizing p53 protein levels, and substantially reducing long-term tumor cell growth (approximately 80%) and colony formation (approximately 95%) in vitro, and inducing apoptosis. However, harboring mutated p53, H322 cell line, was relatively insensitive to such a treatment regimen. Western blot analysis revealed that growth inhibition was associated with increased levels of p53 and p21 protein accumulation. Experiments with subcutaneous tumor in a nu/nu mouse showed the combination treatment to be superior to radiation alone at reducing tumor growth ( approximately 50% reduction as compared to radiation alone) in vivo.
  
  
  CONCLUSIONS
  Thus, our studies confirmed a unique strategy whereby oral administration of a nontoxic estrogen metabolite, 2ME, significantly enhanced the radiation effect on a subcutaneous tumor without any toxicity and suggesting that this strategy may be clinically useful as an adjuvant therapy.
authors.affiliation: Department of Gynecology and Obstetrics, University of Tuebingen, Tuebingen, Germany.
authors.forename: J B
authors.initials: JB
authors.lastname: Huober
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: R
authors.initials: R
authors.lastname: Meyn
authors.forename: J A
authors.initials: JA
authors.lastname: Roth
authors.forename: T
authors.initials: T
authors.lastname: Mukhopadhyay
mesh_terms: D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000532:radiotherapy*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011853:Radiobiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; D000077584:2-Methoxyestradiol