Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer.
Pharm Res
; 29(3): 770-81, 2012 Mar.
Article
in En
| MEDLINE
| ID: mdl-22011930
ABSTRACT
PURPOSE:
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 (14)C-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.METHODS:
Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.RESULTS:
(14)C-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.CONCLUSIONS:
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Quinazolines
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Brain
/
Brain Neoplasms
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Breast Neoplasms
/
Receptor, ErbB-2
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Antineoplastic Agents
Limits:
Animals
Language:
En
Journal:
Pharm Res
Year:
2012
Document type:
Article
Affiliation country:
United States