Profound Prevention of Experimental Brain Metastases of Breast Cancer by Temozolomide in an MGMT-Dependent Manner
| Autor: | Brunilde Gril, Stephan Woditschka, Diane Palmieri, Katarzyna Sosińska-Mielcarek, P. S. Steeg, David J. Liewehr, Stephen M. Hewitt, Emily Hua, Seth M. Steinberg, W. Biernat, Andreas M. Stark, Renata Duchnowska, Jacek Jassem, Yongzhen Qian |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Oncology
Cancer Research Pathology medicine.medical_specialty Dacarbazine Mice Nude Breast Neoplasms Triple Negative Breast Neoplasms Kaplan-Meier Estimate Article Drug Administration Schedule Mice Breast cancer Cell Line Tumor Internal medicine Temozolomide medicine Animals Humans Antineoplastic Agents Alkylating DNA Modification Methylases Dose-Response Relationship Drug Brain Neoplasms business.industry Tumor Suppressor Proteins Cancer medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Primary tumor DNA Repair Enzymes Treatment Outcome MCF-7 Cells Female RNA Interference business Brain metastasis medicine.drug |
| Zdroj: | Clinical Cancer Research. 20:2727-2739 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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 O6-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. Clin Cancer Res; 20(10); 2727–39. ©2014 AACR. |
| Databáze: | OpenAIRE |
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