BORON NEUTRON-CAPTURE THERAPY OF PRIMARY AND METASTATIC BRAIN-TUMORS

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low en ergy (0.025 eV) thermal neutrons (nth) to yield alpha (He-4) particles and Li-7 nuclei (B-10 + n(th) --> [B-11] --> He-4 + Li-7 + 2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the del ivery of a sufficient quantity of B-10 and nth to individual cancer ce lls to sustain a lethal B-10(n, alpha) Li-7 reaction. Boron delivery a gents include a variety of compounds, such as the sulfhydryl containin g polyhedral borane sodium borocaptate (Na2B12H11SH, [BSH]), boronopor phyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three d elivery systems that currently are under investigation in our laborato ries, boronated monoclonal antibodies, carboranyl uridines, and borono phenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a ''starburst'' dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, th ey lose their in vivo tumor localizing properties and accumulate in th e liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-ass ociated antigen and a boronated macromolecule. Boron containing nucleo sides are potential vehicles for incorporating boron compounds into nu cleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthe sized that may have better tumor localizing properties. The potential use of borono-phenylalanine as a capture agent for the treatment of me lanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereota ctically implanted into the brain. BNCT-treated animals have either ha d prolonged survival times or continue to live compared to control rat s that invariably died of their tumors, thereby suggesting therapeutic efficacy.