The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy.
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.
Masunaga
Shin-Ichiro
S
Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan. smasuna@rri.kyoto-u.ac.jp
Nagasawa
Hideko
H
Sakurai
Yoshinori
Y
Uto
Yoshihiro
Y
Hori
Hitoshi
H
Nagata
Kenji
K
Suzuki
Minoru
M
Maruhashi
Akira
A
Kinashi
Yuko
Y
Ono
Koji
K
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
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