title: The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy.
abstract: OBJECTIVE
  To evaluate the usefulness of a new 10B-compound (TX-2100) as a 10B-carrier in boron neutron capture therapy (BNCT), compared with the simultaneous use of its component drugs, sodium borocapate-10B (BSH) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (TX-402). Further, the usefulness of mild temperature hyperthermia (MTH, 40 degrees Celsius, 30 min) combined with TX-2100 was also examined compared with MTH combined with the concurrent administration with its component drugs.
  
  
  METHODS
  TX-2100 is a hybrid compound that has both a hypoxic cytotoxin unit (TX-402) and a thermal neutron-sensitizing unit (BSH). TX-2100 or both TX-402 plus BSH in combination with MTH or not was administered to SCC VII tumour-bearing mice intra-peritoneally. Then, the 10B concentrations in the tumours and normal tissues were measured by gamma-ray spectrometry. Meanwhile, SCC VII tumour-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumours, then treated with TX-2100, TX-402 plus BSH or BSH only, in the same manner as in the biodistribution experiments, either with or without MTH. Right after thermal neutron irradiation during which intra-tumour 10B concentrations remained at similar levels, the tumours were excised, minced and trypsinized. The tumour 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 the total (P + Q) tumour cell population was determined from the tumours that were not pre-treated with BrdU. The clonogenic cell survival was also determined in mice given no BrdU.
  
  
  RESULTS
  10B biodistribution analyses in tumours, brain, skin, muscles, blood and liver indicated that the administration of TX-2100 plus MTH is most favourable for concentrating a sufficient amount of 10B in tumours and maintaining a high enough 10B concentration during irradiation. In addition, MTH had a stronger sensitizing effect when combined with TX-2100 than with the concurrent administration of its components TX-402 and BSH on both the total and Q cell populations in solid tumours.
  
  
  CONCLUSIONS
  MTH was very effective in combination with the newly-developed TX-2100. The sensitizing effect in combination with MTH should be examined when new 10B-carriers are designed.
authors.affiliation: Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Sennan-gun, 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: 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 / Q000494:pharmacology / Q000627:therapeutic use; D001896:Boron Compounds / Q000494:pharmacology / Q000627:therapeutic use; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000628:therapy; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005455:Fluorescent Antibody Technique; D006979:Hyperthermia, Induced; D000860:Hypoxia / Q000503:physiopathology*; D051379:Mice; D008809:Mice, Inbred C3H; D015162:Micronucleus Tests; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use; D013438:Sulfhydryl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: C503709:3-amino-2-quinoxalinecarbonitrile; D001894:Borohydrides; D001896:Boron Compounds; D003497:Cyclic N-Oxides; D011810:Quinoxalines; D011812:Quinuclidines; D013438:Sulfhydryl Compounds; C512407:TX 2100; C014651:mercaptoundecahydrododecaborate