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

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

Author information

1
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.
2
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.
3
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.

Abstract

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.

PMID:
24634373
PMCID:
PMC4100541
DOI:
10.1158/1078-0432.CCR-13-2588
[Indexed for MEDLINE]
Free PMC Article

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