title: Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner.
abstract: OBJECTIVE
  Brain metastases of breast cancer cause neurocognitive damage and are incurable. We evaluated a role for temozolomide in the prevention of brain metastases of breast cancer in experimental brain metastasis models.
  
  
  METHODS
  Temozolomide was administered in mice following earlier injection of brain-tropic HER2-positive JIMT-1-BR3 and triple-negative 231-BR-EGFP sublines, the latter with and without expression of O(6)-methylguanine-DNA methyltransferase (MGMT). In addition, the percentage of MGMT-positive tumor cells in 62 patient-matched sets of breast cancer primary tumors and resected brain metastases was determined immunohistochemically.
  
  
  RESULTS
  Temozolomide, when dosed at 50, 25, 10, or 5 mg/kg, 5 days per week, beginning 3 days after inoculation, completely prevented the formation of experimental brain metastases from MGMT-negative 231-BR-EGFP cells. At a 1 mg/kg dose, temozolomide prevented 68% of large brain metastases, and was ineffective at a dose of 0.5 mg/kg. When the 50 mg/kg dose was administered beginning on days 18 or 24, temozolomide efficacy was reduced or absent. Temozolomide was ineffective at preventing brain metastases in MGMT-transduced 231-BR-EGFP and MGMT-expressing JIMT-1-BR3 sublines. In 62 patient-matched sets of primary breast tumors and resected brain metastases, 43.5% of the specimens had concordant low MGMT expression, whereas in another 14.5% of sets high MGMT staining in the primary tumor corresponded with low staining in the brain metastasis.
  
  
  CONCLUSIONS
  Temozolomide profoundly prevented the outgrowth of experimental brain metastases of breast cancer in an MGMT-dependent manner. These data provide compelling rationale for investigating the preventive efficacy of temozolomide in a clinical setting.
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Diane
authors.initials: D
authors.lastname: Palmieri
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Renata
authors.initials: R
authors.lastname: Duchnowska
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Woditschka
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Emily
authors.initials: E
authors.lastname: Hua
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sosińska-Mielcarek
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Brunilde
authors.initials: B
authors.lastname: Gril
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Stark
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, GermanyAuthors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.affiliation: Authors' Affiliations: Women's Malignancies Branch; Laboratory of Pathology, Center for Cancer Research; Biostatistics and Data Management Section, NCI, NIH, Bethesda; Laboratory Animal Sciences Program, SAIC-Frederick, NCI, NIH, Frederick, Maryland; Department of Oncology, Military Institute of Medicine, Warsaw; Departments of Pathomorphology, and Oncology and Radiotherapy, Medical University; Regional Cancer Center, Gdańsk, Poland; and Klinik fur Neurochirurgie UKSH Campus Kiel, Kiel, Germany steegp@mail.nih.gov.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D034622:RNA Interference; D000077204:Temozolomide; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide