title: The boron-neutron capture agent beta-D-5-o-carboranyl-2'-deoxyuridine accumulates preferentially in dividing brain tumor cells.
abstract: 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 alpha particles, while sparing neighboring non-targeted cells. BNCT treatment of 9L brain tumors in a rat model using beta-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.
authors.affiliation: Department of Nuclear Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
authors.forename: Casey
authors.initials: C
authors.lastname: Moore
authors.forename: Brenda I
authors.initials: BI
authors.lastname: Hernández-Santiago
authors.forename: Selwyn J
authors.initials: SJ
authors.lastname: Hurwitz
authors.forename: Chalet
authors.initials: C
authors.lastname: Tan
authors.forename: Chris
authors.initials: C
authors.lastname: Wang
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D016754:Boron Neutron Capture Therapy; D001932:Brain Neoplasms / Q000378:metabolism* / Q000628:therapy; D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D003857:Deoxyuridine / Q000378:metabolism* / Q000627:therapeutic use; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D011838:Radiation-Sensitizing Agents / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D011838:Radiation-Sensitizing Agents; D003857:Deoxyuridine