title: Neutron capture therapy of intracerebral melanoma: enhanced survival and cure after blood-brain barrier opening to improve delivery of boronophenylalanine.
abstract: OBJECTIVE
  Multicentric cerebral metastases of melanoma represent an important clinical problem for which there currently is no satisfactory treatment. We previously developed a model for melanoma metastatic to the brain employing nude rats bearing intracerebral implants of the human MRA27 melanoma. The purpose of the present study was to determine if the efficacy of boron neutron capture therapy (BNCT) could be improved by either Cereport (RMP-7) mediated modulation of blood-brain barrier (BBB) permeability or hyperosmotic mannitol-induced BBB disruption using boronophenylalanine (BPA) as the capture agent.
  
  
  METHODS
  Biodistribution studies were carried out at 0.5, 2.5, and 4 h after intracarotid administration of Cereport (1.5 microg/kg) and intracarotid or i.v. administration of BPA (500 mg/kg). Peak tumor boron concentrations (65.4 microg/g) and the best composite tumor:brain (6.1:1) and tumor:blood (6.3:1) ratios were observed at 2.5 h after intracarotid administration. BNCT was initiated at the Brookhaven Medical Research Reactor 13-14 days after intracerebral implantation of 10(6) MRA27 cells.
  
  
  RESULTS
  Untreated control rats had a median survival time (MeST) of 22 days and for irradiated controls, it was 30 days. Rats that received i.v. or intracarotid BPA without Cereport followed by BNCT 2.5 h later had MeSTs of 41 days and 57 days, respectively, with 20% long-term survivors (>180 days) in the latter group. Rats that received intracarotid BPA with Cereport had an MeST of 86 days with 36% long-term survivors, which was very close to that of rats that had hyperosmotic mannitol-induced disruption of the BBB (85 days with 25% long-term survivors). When these two groups were combined, and survival times were compared, using the Wilcoxon rank sum test, to those of rats that received intracarotid BPA without blood-brain barrier disruption, these differences were significant at the level p = 0.01.
  
  
  CONCLUSIONS
  Our data show that optimizing the delivery of BPA by means of intracarotid injection combined with opening the BBB by infusing Cereport or a hyperosmotic solution of mannitol significantly enhanced survival times and produced long-term cures of MRA27 melanoma-bearing rats. These observations are relevant to future clinical studies using BNCT for the treatment of intracerebral melanoma.
authors.affiliation: Department of Pathology, Ohio State University, Columbus, OH 43210, USA. barth.1@osu.edu
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Bartus
authors.forename: Joan H
authors.initials: JH
authors.lastname: Rotaru
authors.forename: Amy K
authors.initials: AK
authors.lastname: Ferketich
authors.forename: Melvin L
authors.initials: ML
authors.lastname: Moeschberger
authors.forename: Marta M
authors.initials: MM
authors.lastname: Nawrocky
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Coderre
authors.forename: Einar K
authors.initials: EK
authors.lastname: Rofstad
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016754:Boron Neutron Capture Therapy; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary*; D006801:Humans; D008353:Mannitol / Q000737:chemistry / Q000627:therapeutic use*; D008545:Melanoma / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary*; D009995:Osmosis; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011923:Rats, Nude
chemical_list: D001896:Boron Compounds; D011838:Radiation-Sensitizing Agents; C089876:RMP 7; D008353:Mannitol; D010649:Phenylalanine; D001920:Bradykinin; C033685:4-boronophenylalanine