title: In vitro and in vivo evaluation of o-carboranylalanine as a potential boron delivery agent for neutron capture therapy.
abstract: o-Carboranylalanine (B10H10C2CH2CHNH2COOH) is a carborane-containing amino acid, which has been synthesized as a potential capture agent for boron neutron capture therapy (BNCT) of cancer. The purpose of the present study was to develop a rational approach for the in vitro and in vivo evaluation of boron containing compounds that possibly might be used for BNCT. The in vitro uptake of carboranylalanine (CBA) was evaluated using two cell lines, the human melanoma MRA 27, and the murine Harding-Passey melanoma. Uptake of CBA by MRA 27 cells ranged from 135-551 micrograms B/10(9) cells following 3 hrs incubation with medium containing 100-113 micrograms B/ml and was not reduced by exposing the tumor cells to either rotenone, an inhibitor of electron transport, or by culturing them at ambient temperature (approximately 22 degrees C). Cellular uptake and elution of CBA occurred rapidly under in vitro conditions. Uptake of CBA was slightly greater than that of boronophenylalanine (BPA). Following a 3 hr incubation with CBA at a concentration of 106 micrograms B/ml, cell boron content was 255 micrograms B/10(9) MRA 27 cells, compared to 192 micrograms B/10(9) cells when cells were incubated with BPA at a concentration of 95 micrograms B/ml. In vivo studies initially were carried out using the Harding-Passey melanoma, which had been implanted intramuscularly (i.m.) into the right flank of BALB/c mice. Tumors were allowed to grow for 14 days at which time mice were injected intraperitoneally (i.p.) with either CBA or BPA (1.25 mgB/mouse), and were killed 3, 6 and 8 hrs later. CBA attained a low tumor to blood ratio(1.0-1.4), and the tumor boron levels ranged from 15.7-26.2 micrograms B/g at 3 hrs and 3.3-19.9 micrograms B/g at 6 hrs. Higher blood and lower tumor boron levels were observed at all time points with CBA compared to BPA, suggesting that CBA was not taken up selectively by the melanoma. Similar studies, carried out in rats bearing intra-cerebral gliomas, failed to reveal detectable amounts of boron in the tumor. From the present study, it can be concluded that CBA does not appear to possess the requisite properties to be useful as a boron delivery agent for BNCT.
authors.affiliation: Department of Pathology, Ohio State University, Columbus 43210, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Yong
authors.forename: R F
authors.initials: RF
authors.lastname: Barth
authors.forename: I M
authors.initials: IM
authors.lastname: Wyzlic
authors.forename: A H
authors.initials: AH
authors.lastname: Soloway
authors.forename: J H
authors.initials: JH
authors.lastname: Rotaru
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics*; D016754:Boron Neutron Capture Therapy; D003505:Cyclodextrins / Q000494:pharmacology; D005260:Female; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D047392:beta-Cyclodextrins
chemical_list: D001896:Boron Compounds; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D012402:Rotenone; D010649:Phenylalanine; C031215:betadex; C033685:4-boronophenylalanine