title: Vinorelbine Delivery and Efficacy in the MDA-MB-231BR Preclinical Model of Brain Metastases of Breast Cancer.
abstract: To evaluate vinorelbine drug exposure and activity in brain metastases of the human MDA-MB-231BR breast cancer model using integrated imaging and analysis.
  
  
  
  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.
  
  
  
  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,uuapproached 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 IC50for 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.
  
  
  
  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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 South Coulter Drive, Amarillo, Texas, 79106, USA.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Samala
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 South Coulter Drive, Amarillo, Texas, 79106, USA.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Thorsheim
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 South Coulter Drive, Amarillo, Texas, 79106, USA.|Formurex, Inc., Stockton, California, 95215, USA.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Goda
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 South Coulter Drive, Amarillo, Texas, 79106, USA.|Mechanistic Safety and Disposition, IVIVT, GlaxoSmithKline, Ware, Hertfordshire, SG12 0DP, UK.
authors.forename: Kunal
authors.initials: K
authors.lastname: Taskar
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892, USA.
authors.forename: Brunilde
authors.initials: B
authors.lastname: Gril
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892, USA.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 South Coulter Drive, Amarillo, Texas, 79106, USA. quentin.smith@ttuhsc.edu.
authors.forename: Quentin R
authors.initials: QR
authors.lastname: Smith
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D008819:Mice, Nude; D010539:Permeability; D014018:Tissue Distribution; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D014747:Vinblastine; D000077235:Vinorelbine
keywords: blood–brain barrier; brain metastases; breast cancer; permeability; vinorelbine