The Boron–Neutron Capture Agent β-d-5-o-Carboranyl-2′-deoxyuridine Accumulates Preferentially in Dividing Brain Tumor Cells

Boron–neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with 10B and subsequent irradiation with epithermal neutrons to produce a highly localized field of lethal α particles, while sparing neighboring non-targeted cells. BNCT treatment of 9L brain tumors in a rat model using β-d-5-o-carboranyl-2′-deoxyuridine (d-CDU) resulted in greater efficacy than predicted based on the assumption of a uniform tumor distribution of 10B. Thus, the geometric heterogeneity of dividing cells in brain tumors warranted studies on the cell cycle dependency of d-CDU accumulation, metabolism and entrapment in a relevant brain tumor cell system. U-271 human glioma cells were synchronized in G1 or S-phases of the cell cycle. The cellular accumulation and phosphorylation of d-CDU was measured in the G1 and S-phase cells using high-performance liquid chromatography (HPLC). Cells synchronized in the S-phase accumulated significantly higher amounts of d-CDU and produced larger amounts of negatively charged d-CDU monophosphate (d-CDU-MP) and nido-CDU metabolites than resting cells. Since brain tumors contain a larger proportion of cycling cells than neighboring tissue, these results support the hypothesis that in addition to breakdown of the blood-brain-barrier (BBB) in tumors, the preferential phosphorylation of d-CDU in cycling cells may further enrich the distribution of 10B in dividing cells. Therefore, dosimetry calculations that include the spatial distribution of cycling cells may be warranted for d-CDU.