In vitro and in vivo evaluation of carboranyl uridines as boron delivery agents for neutron capture therapy.

摘要: The purpose of the present study was to evaluate 2' and 5'-O-(o-carboran-1-ylmethyl)uridine (CBU-2' CBU-5') as delivery agents for Boron Neutron Capture Therapy (BNCT) brain tumors. in vitro cellular uptake, persistence, subcellular distribution cytotoxicity, vivo biodistribution CBU-2' have been studied follows. Cellular uptake studies were carried out with F98 rat glioma, U-87 MG human B16 melanoma, SP2/0 myeloma MDCK fibroblasts. All tumor non-tumor cell lines had high (46-75 ppm), indicating that not selective neoplastic cells independent proliferation. In persistence showed retention compared sodium borocaptate (BSH), when transferred from boron-containing boron-free medium cultured an additional 24-48 hours. Subcellular fractionation revealed 75.6% recoverable boron membrane associated, 15.6% cytosol, 8.8% nuclear fraction, but no detectable RNA DNA fractions. glioma presence 3 metabolic inhibitors (rotenone, dipyridamole NBMPR ?6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine?) none these blocked suggesting neither energy nor nucleoside transport dependent. bearing rats attained concentrations 8.0 +/- 2.1 micrograms B/g tissue, which 13 x greater than normal ipsilateral contralateral cerebral hemispheres (0.6 0.2 microgram B/g). B levels, however, still lower minimum 20-35 B/g, are required BNCT. summary, our data indicate sufficiently targeting However, CBU-5' highly toxic (IC50 = - 10(-5) M), determined by measuring 3H-thymidine, survival using a clonogenic assay, suggests compounds should be further evaluated potential cytoreductive chemotherapeutic agents.