Evaluation of the potential of p-boronophenylalaninol as a boron carrier in boron neutron capture therapy, referring to the effect on intratumor quiescent cells.
C57BL mice bearing EL4 tumors and C3H / He mice bearing SCC VII tumors received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps to label all proliferating (P) cells. Three hours after oral administration of l-p-boronophenylalanine-(10)B (BPA), or 30 min after intraperitoneal injection of sodium borocaptate-(10)B (BSH) or l-p-boronophenylalaninol (BPA-ol), a newly developed (10)B-containing alpha-amino alcohol, the tumors were irradiated with thermal neutron beams. For the combination with mild temperature hyperthermia (MTH) and / or tirapazamine (TPZ), the tumors were heated at 40 degrees C for 30 min immediately before neutron exposure, and TPZ was intraperitoneally injected 30 min before irradiation. The tumors were then 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 labeling ( = quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. Meanwhile, 6 h after irradiation, tumor cell suspensions obtained in the same manner were used for determining the apoptosis frequency in Q cells. The MN and apoptosis frequency in total (P + Q) tumor cells were determined from tumors that were not pretreated with BrdU. Without TPZ or MTH, BPA-ol increased both frequencies most markedly, especially for total cells. However, as with BPA, the sensitivity difference between total and Q cells was much larger than with BSH. On combined treatment with both MTH and TPZ, this sensitivity difference was markedly reduced, similarly to when BPA was used. MTH increased the (10)B uptake of all (10)B-compounds into both tumor cells. BPA-ol has good potential as a (10)B-carrier in neutron capture therapy, especially when combined with both MTH and TPZ.
Masunaga
S I
SI
Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Noda, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan. smasuna@rri.kyoto-u.ac.jp
Ono
K
K
Kirihata
M
M
Takagaki
M
M
Sakurai
Y
Y
Kinashi
Y
Y
Kobayashi
T
T
Nagasawa
H
H
Uto
Y
Y
Hori
H
H
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001880:Boranes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000528:radiation effects; D016754:Boron Neutron Capture Therapy; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003571:Cytochalasin B / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D019084:Fluorescent Antibody Technique, Indirect; D006614:Hindlimb; D006979:Hyperthermia, Induced; D007274:Injections, Intraperitoneal; D007399:Interphase; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015162:Micronucleus Tests; D015394:Molecular Structure; D009502:Neutrons; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics* / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use; D011874:Radiometry; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001880:Boranes; D011838:Radiation-Sensitizing Agents; D014227:Triazines; C447034:boronophenylalaninol; D000077704:Tirapazamine; D003571:Cytochalasin B; D010649:Phenylalanine; D001973:Bromodeoxyuridine