title: NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer.
abstract: BACKGROUND
  Brain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity.
  
  
  METHODS
  Female nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively).
  
  
  RESULTS
  NKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (>20 ng/g for 168 h) versus conventional irinotecan (>1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals.
  
  
  CONCLUSIONS
  Elevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m(2) NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results.
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, WV, 26506-905, USA. ciadkins@hsc.wvu.edu.|School of Pharmacy, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA. ciadkins@hsc.wvu.edu.
authors.forename: Chris E
authors.initials: CE
authors.lastname: Adkins
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA. nounou@alexu.edu.eg.|Faculty of Pharmacy, Department of Pharmaceutics, Alexandria University, Alexandria, Egypt. nounou@alexu.edu.eg.
authors.forename: Mohamed I
authors.initials: MI
authors.lastname: Nounou
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA. tanvirul.hye@ttuhsc.edu.
authors.forename: Tanvirul
authors.initials: T
authors.lastname: Hye
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, WV, 26506-905, USA. asmohammad@mix.wvu.edu.|School of Pharmacy, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA. asmohammad@mix.wvu.edu.
authors.forename: Afroz S
authors.initials: AS
authors.lastname: Mohammad
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, WV, 26506-905, USA. tbterrell@mix.wvu.edu.|School of Pharmacy, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA. tbterrell@mix.wvu.edu.
authors.forename: Tori
authors.initials: T
authors.lastname: Terrell-Hall
authors.affiliation: Nektar Therapeutics, San Francisco, CA, 94158, USA. nmohan@nektar.com.
authors.forename: Neel K
authors.initials: NK
authors.lastname: Mohan
authors.affiliation: Nektar Therapeutics, San Francisco, CA, 94158, USA. meldon@nektar.com.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eldon
authors.affiliation: Nektar Therapeutics, San Francisco, CA, 94158, USA. UHoch@nektar.com.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, WV, 26506-905, USA. prlockman@hsc.wvu.edu.|School of Pharmacy, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA. prlockman@hsc.wvu.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008163:Luminescent Measurements; D051379:Mice; D015394:Molecular Structure; D010539:Permeability; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin