Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer
| Autor: | Stephen D. Rubin, Vinay Rudraraju, Kunal S Taskar, Emily Hua, Diane Palmieri, Ramakrishna Samala, Brunilde Gril, Stephen Castellino, Paul R. Lockman, Julie A. Lockman, Patricia S. Steeg, Quentin R. Smith, Joseph W. Polli, Helen R. Thorsheim, Rajendar K. Mittapalli |
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| Rok vydání: | 2011 |
| Předmět: |
Oncology
medicine.medical_specialty Receptor ErbB-2 Administration Oral Pharmaceutical Science Antineoplastic Agents Breast Neoplasms Lapatinib Article Mice Breast cancer Oral administration Cell Line Tumor Internal medicine medicine Animals Distribution (pharmacology) Neoplasm Pharmacology (medical) skin and connective tissue diseases Receptor Pharmacology Brain Neoplasms business.industry Organic Chemistry Brain medicine.disease Up-Regulation Drug Resistance Neoplasm Injections Intravenous Quinazolines Molecular Medicine Female business Ex vivo Biotechnology Brain metastasis medicine.drug |
| Zdroj: | Pharmaceutical Research. 29:770-781 |
| ISSN: | 1573-904X 0724-8741 |
| Popis: | Lapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following 14C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography. 14C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7–9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, average lapatinib concentration in brain metastases was still only 10–20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains. Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors. |
| Databáze: | OpenAIRE |
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