title: Applicability of the 2-nitroimidazole-sodium borocaptate-10B conjugate, TX-2060, as a 10B-carrier in boron neutron capture therapy.
abstract: BACKGROUND
  It is difficult to deliver a therapeutic amount of 10B from conventional 10B-carriers for boron neutron capture therapy (BNCT) throughout the target tumors, especially into the intratumor hypoxic cells which have low uptake capacities. We evaluated the usefulness of 5 new 10B-compounds (TX-2041, TX-2042, TX-2058, TX-2059 and TX-2060) as 10B-carriers in BNCT. They are 2-nitroimidazole-sodium borocaptate-10B (BSH) conjugates, that is, hybrid compounds that have both a hypoxic tumor cell sensitizing unit under gamma-ray irradiation, 2-nitroimidazoles and a thermal neutron-sensitizing unit, BSH.
  
  
  METHODS
  The 5 new compounds were administered to SCC VII tumor-bearing mice intraperitoneally. As a control, BSH was also administered in the same manner. Then, the 10B concentrations in the tumors and normal tissues were measured by gamma-ray spectrometry. Based on the data of the pharmacokinetics analyses, TX-2060 was chosen for a subsequent tumor-irradiation study. SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2060 or BSH in the same manner as in the pharmacokinetics analyses. To obtain similar intratumor 10B concentrations during radiation exposure, irradiation with thermal neutrons or gamma-rays was started from 60 min after administration of the 10B-carrier. Right after irradiation, the tumors were excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU-labelling (= quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in total (P + Q) tumor cells was determined from the tumors that were not pretreated with BrdU. The clonogenic cell survival was also determined in mice given no BrdU.
  
  
  RESULTS
  10B distribution analyses in tumors, muscles, blood and liver indicated that TX-2060 has the most favorable characteristics for concentrating a sufficient amount of 10B in tumors and maintaining a high enough 10B concentration during irradiation. In addition, TX-2060 had a significantly stronger radio-sensitization effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2060 clearly exhibited a radio-sensitization effect with gamma-rays, not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH.
  
  
  CONCLUSIONS
  10B-carrier, with a gamma-ray-sensitizing effect on tumor cells as well as the potential to keep 10B in tumors and sensitize tumor cells more markedly than conventional 10B-carriers, such as TX-2060, is a promising candidate for use in BNCT.
authors.affiliation: Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Osaka, Japan. smasuna@rri.kyoto-u.ac.jp
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Masunaga
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Hiraoka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
authors.forename: Kenji
authors.initials: K
authors.lastname: Nagata
authors.forename: Minoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Maruhashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kinashi
authors.forename: Koji
authors.initials: K
authors.lastname: Ono
mesh_terms: D000818:Animals; D001894:Borohydrides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001895:Boron / Q000737:chemistry; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy*; D005260:Female; D007554:Isotopes; D051379:Mice; D008809:Mice, Inbred C3H; D015162:Micronucleus Tests; D009593:Nitroimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D001894:Borohydrides; D007554:Isotopes; D009593:Nitroimidazoles; D013438:Sulfhydryl Compounds; C493830:TX-2060; C014651:mercaptoundecahydrododecaborate; D001895:Boron