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Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer

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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 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.

Methods

Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.

Results

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.

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.

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Abbreviations

BBB:

blood–brain barrier

BCRP:

breast cancer resistance protein

BTB:

blood-tumor barrier

CNS:

central nervous system

EGFP:

enhanced green fluorescent protein

EGFR:

epidermal growth factor receptor

MRP:

multidrug resistance protein

P-gp:

p-glycoprotein

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ACKNOWLEDGMENTS & DISCLOSURES

Drs. Rubin, Castellino, and Polli work for GlaxoSmithKline, which owns the patent to lapatinib, and thus have a financial interest.

Grant Support

Intramural Program of the National Cancer Institute (P.S.S., D.P.), grant W81XWH-062-0033 from the Department of Defense Breast Cancer Research Program (P.S.S., Q.R.S., P.R.L., and D.P.), grants R01 NS052484 and R01 NS052484-04S1 from NINDS/NIH (Q.R.S.) and GlaxoSmithKline grant to Q.R.S.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, Texas, 79106, USA

    Kunal S. Taskar, Vinay Rudraraju, Rajendar K. Mittapalli, Ramakrishna Samala, Helen R. Thorsheim, Paul R. Lockman & Quentin R. Smith

  2. Department of Biological Sciences, West Texas A&M University, Canyon, Texas, 79016, USA

    Julie Lockman

  3. Women’s Cancers Section, Laboratory of Molecular Pharmacology National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Brunilde Gril, Emily Hua, Diane Palmieri & Patricia S. Steeg

  4. GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, USA

    Joseph W. Polli & Stephen Castellino

  5. GlaxoSmithKline, Collegeville, Pennsylvania, 19426, USA

    Stephen D. Rubin

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  1. Kunal S. Taskar
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Corresponding author

Correspondence to Quentin R. Smith.

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Taskar, K.S., Rudraraju, V., Mittapalli, R.K. et al. Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer. Pharm Res 29, 770–781 (2012). https://doi.org/10.1007/s11095-011-0601-8

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  • DOI: https://doi.org/10.1007/s11095-011-0601-8

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