Biodistribution of boron compounds in an animal model of human undifferentiated thyroid cancer for boron neutron capture therapy.
Undifferentiated thyroid carcinoma (UTC) is a rapidly growing, highly invasive malignant tumor that currently lacks any effective treatment. Boron neutron capture therapy (BNCT) has been investigated recently for some types of tumors including glioblastoma multiforme and malignant melanoma. In previous studies we have shown the selective uptake of p-boronophenylalanine (BPA) by undifferentiated thyroid cancer cells in vitro and in vivo, as well as the histologic cure of 50% of the nude mice transplanted with human UTC cells when treated with BPA and an appropriate neutron beam. The present studies were performed to further optimize this treatment through the investigation of a boronated porphyrin, both alone and in combination with BPA. In vitro studies with cells in culture showed that BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(alpha,beta-dihydroxyethyl)-deutero-porphyrin IX) is localized intracellularly, with a highest concentration in the 11500g (mitochondrial-enriched pellet) fraction. When BOPP was administered alone to NIH nude mice transplanted with UTC human cells, no significant tumor uptake or selectivity in our in vivo model was observed. In contrast, when BOPP was injected 5-7 days before BPA and the animals were sacrificed 60 min after administration of BPA, a significant increase in boron uptake by the tumor was found (38-45 ppm with both compounds vs 20 ppm with BPA alone). On day 5 the tissue boron selectivity ratios were tumor/blood approximately 3.8 and tumor/distal skin approximately 1.8. Other important ratios were tumor/thyroid approximately 6.6 and tumor/lung approximately 2.9. These results open the possibility of improving the efficacy of BNCT for the treatment of this so far "orphan" tumor.
Dagrosa
M Alejandra
MA
Departments of Radiobiology and Chemistry, National Atomic Energy Commission, Av. del Libertador 8250, Buenos Aires 1429, Argentina.
Viaggi
Mabel
M
Rebagliati
Raul Jimenez
RJ
Batistoni
Daniel
D
Kahl
Stephen B
SB
Juvenal
Guillermo J
GJ
Pisarev
Mario A
MA
D000818:Animals; D001895:Boron / Q000737:chemistry; D001896:Boron Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003905:Deuteroporphyrins / Q000494:pharmacology; D004195:Disease Models, Animal; D005632:Fructose / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D013997:Time Factors; D014018:Tissue Distribution; D000098851:Carboranes
D001895:Boron; D001896:Boron Compounds; D003905:Deuteroporphyrins; D005632:Fructose; D010649:Phenylalanine; C080251:2,4-(alpha,beta-dihydroxyethyl)deuteroporphyrin IX tetrakiscarborane carboxylate ester; D000098851:Carboranes; C033685:4-boronophenylalanine