Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner

Clin Cancer Res. 2014 May 15;20(10):2727-39. doi: 10.1158/1078-0432.CCR-13-2588. Epub 2014 Mar 14.


Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / prevention & control*
  • Brain Neoplasms / secondary
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • DNA Modification Methylases / genetics
  • DNA Modification Methylases / metabolism*
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • RNA Interference
  • Temozolomide
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents, Alkylating
  • Tumor Suppressor Proteins
  • Dacarbazine
  • DNA Modification Methylases
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide