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Vinorelbine Delivery and Efficacy in the MDA-MB-231BR Preclinical Model of Brain Metastases of Breast Cancer

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Abstract

Purpose

To evaluate vinorelbine drug exposure and activity in brain metastases of the human MDA-MB-231BR breast cancer model using integrated imaging and analysis.

Methods

Brain and systemic metastases were created by administration of cancer cells in female NuNu mice. After metastases developed, animals were administered vinorelbine at the maximal tolerated dose (12 mg/kg), and were evaluated thereafter for total and unbound drug pharmacokinetics, biomarker TUNEL staining, and barrier permeability to Texas red.

Results

Median brain metastasis drug exposure was 4-fold greater than normal brain, yet only ~8% of non-barrier systemic metastases, which suggests restricted brain exposure. Unbound vinorelbine tissue/plasma partition coefficient, Kp,uu, equaled ~1.0 in systemic metastases, but 0.03–0.22 in brain metastases, documenting restricted equilibration. In select sub-regions of highest drug-uptake brain metastases, Kp,uu approached 1.0, indicating complete focal barrier breakdown. Most vinorelbine-treated brain metastases exhibited little or no positive early apoptosis TUNEL staining in vivo. The in vivo unbound vinorelbine IC50 for TUNEL-positive staining (56 nM) was 4-fold higher than that measured in vitro (14 nM). Consistent with this finding, P-glycoprotein expression was observed to be substantially upregulated in brain metastasis cells in vivo.

Conclusions

Vinorelbine exposure at maximum tolerated dose was less than one-tenth that in systemic metastases in >70% of brain metastases, and was associated with negligible biomarker effect. In small subregions of the highest uptake brain metastases, compromise of blood-tumor barrier appeared complete. The results suggest that restricted delivery accounts for 80% of the compromise in drug efficacy for vinorelbine against this model.

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Abbreviations

AUC:

Area under the curve

BAT:

Brain adjacent to tumor

BBB:

Blood–brain barrier

BTB:

Blood-tumor barrier

CNS:

Central nervous system

fu :

Unbound fraction

fu,hd :

Unbound fraction in diluted homogenate

Kp :

Integrated total drug partition coefficient between tissue and plasma

Kp , uu :

Integrated unbound drug partition coefficient between tissue and plasma

PD:

Pharmacodynamics

P-gp:

P-glycoprotein (ABCB1)

PK:

Pharmacokinetics

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by grants from the Department of Defense Breast Cancer Program (W81XWH-06-2-0033) and the Cancer Prevention Research Institute of Texas (RP120489 and RP110786)

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 South Coulter Drive, Amarillo, Texas, 79106, USA

    Ramakrishna Samala, Helen R. Thorsheim, Satyanarayana Goda, Kunal Taskar & Quentin R. Smith

  2. Formurex, Inc., Stockton, California, 95215, USA

    Satyanarayana Goda

  3. Mechanistic Safety and Disposition, IVIVT, GlaxoSmithKline, Ware, Hertfordshire, SG12 0DP, UK

    Kunal Taskar

  4. Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892, USA

    Brunilde Gril & Patricia S. Steeg

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  1. Ramakrishna Samala
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  2. Helen R. Thorsheim
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Correspondence to Quentin R. Smith.

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Samala, R., Thorsheim, H.R., Goda, S. et al. Vinorelbine Delivery and Efficacy in the MDA-MB-231BR Preclinical Model of Brain Metastases of Breast Cancer. Pharm Res 33, 2904–2919 (2016). https://doi.org/10.1007/s11095-016-2012-3

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  • DOI: https://doi.org/10.1007/s11095-016-2012-3

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