title: Penetration and binding of L- and D-carboranylalanine in human melanoma spheroids.
abstract: The principle of boron neutron capture therapy (BNCT) is that a cell-specific 10B-containing substance binds to tumour cells and irradiation with thermal neutrons is performed when the 10B concentration, in relation to the levels in critical normal tissues, is at a maximum. Some boron compounds have recently been proposed for BNCT of malignant melanomas; the synthesized L- and D- forms of carboranylalanine and the previously tested compound L-p-boronophenylalanine are candidates. Human melanoma, IGR1, spheroids were used as models of melanoma nodules in this study. The spheroids developed central necrosis when they were about 480 microns in diameter and the volume doubling time was 2.6 +/- 0.3 days. The tritiated thymidine labelling index decreased rapidly as a function of distance from the periphery and was, at a depth of 175 microns, close to zero. The penetration patterns showed, for L- and D-carboranylalanine and L-p-boronophenylalanine, a homogeneous distribution of 10B throughout the spheroids by 5 min. L-Carboranylalanine gave a more or less even binding of 10B throughout the spheroids and large amounts were present also in the central necrotic regions. D-Carboranylalanine also gave a homogeneous 10B binding in the viable cell layers while the binding in the central necrotic area was lower and a similar, but somewhat lower, binding was found for L-p-boronophenylalanine. Thus, there were no penetration barriers for the boron compounds and binding of 10B was found also in the deeper regions of the viable cell layers. The results showed that the new carboranylalanine compounds are of interest for further analysis, including toxicological and pharmacological studies in vivo.
authors.affiliation: Department of Radiation Sciences, Uppsala University, Sweden.
authors.forename: O A
authors.initials: OA
authors.lastname: Pettersson
authors.forename: P
authors.initials: P
authors.lastname: Olsson
authors.forename: P
authors.initials: P
authors.lastname: Lindström
authors.forename: S
authors.initials: S
authors.lastname: Sjöberg
authors.forename: J
authors.initials: J
authors.lastname: Carlsson
mesh_terms: D001896:Boron Compounds / Q000378:metabolism* / Q000493:pharmacokinetics*; D016754:Boron Neutron Capture Therapy; D002449:Cell Aggregation; D002453:Cell Cycle / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014407:Tumor Cells, Cultured
chemical_list: D001896:Boron Compounds; D011838:Radiation-Sensitizing Agents; D014316:Tritium; D010649:Phenylalanine; C014388:carboranylalanine; C033685:4-boronophenylalanine; D013936:Thymidine