Treatment of isografted 9L rat brain tumors with beta-5-o-carboranyl-2 '-deoxyuridine neutron capture therapy

beta-5-o-Carboranyl-2'-deoxyuridine (D-CDU) is a nontoxic pyrimidine nucleo side analogue designed for boron neutron capture therapy of brain tumors. I rt vitro studies indicated that D-CDU accumulates to levels 92- and 117-fol d higher than the extracellular concentration in rat 9L and human U-251 gli oma cells, respectively, and persists for several hours at levels 5-fold hi gher than the extracellular concentration. Furthermore, D-CDU was not toxic to rats injected i.p. with up to 150 mg/kg, On the basis of these studies, D-CDU was evaluated as a neutron capture therapy agent using rats bearing stereotactically implanted intracranial 9L, tumors at single i.p. doses of 30 mg/kg and 150 mg/kg of D-CDU (20% B-10 enriched), given 2 h before irrad iation with thermal neutrons, Boron concentrations in tumors 2 h after dosi ng were 2.3 +/- 1.6 and 7.4 +/- 1.3 Erg boron/g tissue (mean +/- SD), corre sponding to tumor/brain ratios of 11.5 +/- 3.6 and 6.8 +/- 2.0 mu g boron/g tissue for the low and high doses, respectively. All untreated animals die d within 28 days, whereas half survived at days 32, 55, and 38 for groups r eceiving neutrons only, 30 mg/kg D-CDU, and 150 mg/kg D-CDU, respectively. Odds ratios of all treatment groups differed significantly from the untreat ed group (P < 0.002; logrank test). The median survival time for the 30 mg/ kg-treated group but not for the 150 mg/kg-treated group was significantly longer than for rats treated with neutrons only (P = 0.036), which may corr elate with the decreased tumor selectivity for D-CDU observed at the higher dose. Additional pharmacodynamic studies are warranted to determine optima l dosing strategies for D-CDU.