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

Summary Boron–neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with 10 B 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 10 B. 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 G 1 or S-phases of the cell cycle. The cellular accumulation and phosphorylation of d -CDU was measured in the G 1 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 10 B in dividing cells. Therefore, dosimetry calculations that include the spatial distribution of cycling cells may be warranted for d -CDU.