Optimization of boron neutron capture therapy for the treatment of undifferentiated thyroid cancer.
OBJECTIVE
To analyze the possible increase in efficacy of boron neutron capture therapy (BNCT) for undifferentiated thyroid carcinoma (UTC) by using p-boronophenylalanine (BPA) plus 2,4-bis (alpha,beta-dihydroxyethyl)-deutero-porphyrin IX (BOPP) and BPA plus nicotinamide (NA) as a radiosensitizer of the BNCT reaction.


METHODS
Nude mice were transplanted with a human UTC cell line (ARO), and after 15 days they were treated as follows: (1) control, (2) NCT (neutrons alone), (3) NCT plus NA (100 mg/kg body weight [bw]/day for 3 days), (4) BPA (350 mg/kg bw) + neutrons, (5) BPA + NA + neutrons, and (6) BPA + BOPP (60 mg/kg bw) + neutrons. The flux of the mixed (thermal + epithermal) neutron beam was 2.8 x 10(8) n/cm(2)/sec for 83.4 min.


RESULTS
Neutrons alone or with NA caused some tumor growth delay, whereas in the BPA, BPA + NA, and BPA + BOPP groups a 100% halt of tumor growth was observed in all mice at 26 days after irradiation. When the initial tumor volume was 50 mm(3) or less, complete remission was found with BPA + NA (2 of 2 mice), BPA (1 of 4), and BPA + BOPP (7 of 7). After 90 days of complete regression, recurrence of the tumor was observed in BPA + NA (2 of 2) and BPA + BOPP (1 of 7). The determination of apoptosis in tumor samples by measurements of caspase-3 activity showed an increase in the BNCT (BPA + NA) group at 24 h (p < 0.05 vs. controls) and after the first week after irradiation in the three BNCT groups. Terminal transferase dUTP nick end labeling analysis confirmed these results.


CONCLUSIONS
Although NA combined with BPA showed an increase of apoptosis at early times, only the group irradiated after the combined administration of BPA and BOPP showed a significantly improved therapeutic response.
Dagrosa
Maria Alejandra
MA
Department of Radiobiology (Constituyentes Atomic Center), National Atomic Energy Commission of Argentina, Buenos Aires, Argentina.
Thomasz
Lisa
L
Longhino
Juan
J
Perona
Marina
M
Calzetta
Osvaldo
O
Blaumann
Herman
H
Rebagliati
Raúl Jiménez
RJ
Cabrini
Romulo
R
Kahl
Steven
S
Juvenal
Guillermo Juan
GJ
Pisarev
Mario Alberto
MA
D000818:Animals; D017209:Apoptosis; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D045744:Cell Line, Tumor; D003905:Deuteroporphyrins / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000627:therapeutic use*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D012074:Remission Induction; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D014018:Tissue Distribution; D000098851:Carboranes
D001896:Boron Compounds; D003905:Deuteroporphyrins; D009536:Niacinamide; D010649:Phenylalanine; D011838:Radiation-Sensitizing Agents; C080251:2,4-(alpha,beta-dihydroxyethyl)deuteroporphyrin IX tetrakiscarborane carboxylate ester; D000098851:Carboranes; C033685:4-boronophenylalanine