title: Radiobiological evidence suggesting heterogeneous microdistribution of boron compounds in tumors: its relation to quiescent cell population and tumor cure in neutron capture therapy.
abstract: OBJECTIVE
  The heterogeneous microdistribution of boron compounds in tumors and its significance on tumor cure were examined by a radiobiological procedure. The role of quiescent (Q) cells in tumor was especially investigated.
  
  
  METHODS
  10B-enriched paraboronophenylalanine (BPA) and mercaptoundecahydrododecaborate (BSH) were administered to SCCVII tumor bearing C3H/He mice by intragastric and i.v. injections, respectively. The continued effects of these boron compounds with thermal irradiations were studied by using colony formation and tumor control assays. Their effects on Q cells were also analyzed by the combined method of micronucleus frequency assay and an identification of proliferating (P) cells by BUdR and anti-BUdR monoclonal antibody.
  
  
  RESULTS
  10B-concentration after BPA (1,500 mg/kg) and BSH (75 mg/kg) administration were 11 ppm at 3 h and 10.5 ppm at 30 min, respectively. Cell survival decreased exponentially with an increment of neutron fluence (phi). The exponential parts of the curves were: -InSF = -0.052+ 13.0x10(13)phi, -InSF = -0.032+7.68X10(-13)phi, and -InSF = -0.0005+2.68x10(-13)phi for BPA-BNCT, BSH-BNCT, and NCT alone, respectively. Fifty percent tumor control was obtained at the influence of 10.2 x 10(12) n/cm2 in BPA-BNCT. On the other hand, 11.4 x 10(12) n/cm2 of neutrons had to be delivered in BSH-BNCT. The normal nuclear division fraction defined as the cell fraction that did not express micronuclei at first mitosis after treatment was investigated. The surviving cell fraction and the normal nuclear division fraction were regarded as equal in NCT alone. However, the normal nuclear division factor following BPA-BNCT was greater than the surviving cell fraction, and the difference increased with an increase in neutron fluence. In Q cells, BSH-BNCT yielded higher micronucleus frequency than BPA-BNCT and NCT alone. The frequencies in Q cells following BPA-BNCT and NCT alone were almost same as that in total cell population after NCT alone.
  
  
  CONCLUSIONS
  Our data suggested that BPA distributed in tumors hetergeneously. Q cells especially might not accumulate BPA. To decrease the possible disadvantage of BPA-BNCT, the combination of BPA and BSH or other neutron capture element that emit particles with longer ranges, for example, gadolinium, would have to be investigated.
authors.affiliation: Research Reactor Institute, Kyoto University, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ono
authors.forename: S I
authors.initials: SI
authors.lastname: Masunaga
authors.forename: Y
authors.initials: Y
authors.lastname: Kinashi
authors.forename: M
authors.initials: M
authors.lastname: Takagaki
authors.forename: M
authors.initials: M
authors.lastname: Akaboshi
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Akuta
mesh_terms: D000818:Animals; D001881:Borates / Q000097:blood / Q000493:pharmacokinetics*; D001896:Boron Compounds / Q000097:blood / Q000493:pharmacokinetics*; D016754:Boron Neutron Capture Therapy; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000378:metabolism*; D002470:Cell Survival; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015162:Micronucleus Tests; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D001881:Borates; D001896:Boron Compounds