Skip to main content

Advertisement

SpringerLink
Log in

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

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • RF Barth AH Soloway RG Fairchild RM Brugger (1992) ArticleTitleBoron neutron capture therapy for cancer. Realities and prospects Cancer 70 2995–3007 Occurrence Handle1451084

    PubMed  Google Scholar 

  • AH Soloway W Tjarks BA Barnum F Rong RF Barth IM Codognic JG Wilson (1998) ArticleTitleThe chemistry of neutron capture therapy Chem Rev 98 1515–1562 Occurrence Handle10.1021/cr941195u Occurrence Handle11848941

    Article  PubMed  Google Scholar 

  • JA Coderre GM Morris (1999) ArticleTitleThe radiation biology of boron neutron capture therapy Radiat Res 151 1–18 Occurrence Handle9973079

    PubMed  Google Scholar 

  • RF Barth (2003) ArticleTitleA critical assessment of boron neutron capture therapy:an overview J Neurooncol 62 1–5 Occurrence Handle10.1023/A:1023262817500 Occurrence Handle12749698

    Article  PubMed  Google Scholar 

  • SC Mehta DR Lu (1996) ArticleTitleTargeted drug delivery for boron neutron capture therapy Pharm Res 13 344–351 Occurrence Handle10.1023/A:1016076022267 Occurrence Handle8692724

    Article  PubMed  Google Scholar 

  • I Kato K Ono Y Sakurai M Ohmae A Maruhashi Y Imahori M Kirihata M Nakazawa Y Yura (2003) ArticleTitleEffectiveness of BNCT for recurrent head and neck malignancies Appl Radiat Isotopes 61 1069–1073 Occurrence Handle10.1016/j.apradiso.2004.05.059

    Article  Google Scholar 

  • Y Nakagawa K Pooh T Kobiyashi T Kagiji S Uyama A Matsamura H Kumada (2003) ArticleTitleClinical review of the Japanese experience with boron neutron capture therapy and proposed strategy using epithermal neutron beams. J Neurooncol 62 87–99 Occurrence Handle10.1023/A:1023234902479 Occurrence Handle12749705

    Article  PubMed  Google Scholar 

  • H Joensuu L Kankaanranta T Seppala I Auterinen M Kallio M Kulvik J Laaksu J Vahatalo M Kortesniemi P Kotiluoto T Seren J Karili A Brander E Jarviluoma P Ryynanen A Paetau I Ruokenen H Minn M Tenhunen J Jaaskelainen M Farkkila S Savolainen (2003) ArticleTitleBoron neutron capture therapy of brain tumors: clinical trials at the Finnish facility using boranophenylalanine J Neurooncol 62 123–134 Occurrence Handle10.1023/A:1023293006617 Occurrence Handle12749708

    Article  PubMed  Google Scholar 

  • J Capala B H-Stenstam K Skold RM af Rosenschold V Giusti C Persson E Wallin A Brun L Franzen J Carlsson L Salford C Ceberg B Persson l Pellettieri R Henriksson (2003) ArticleTitleBoron neutron capture therapy for glipblastoma multiforme: clinical studies in Sweden J Neurooncol 62 135–144 Occurrence Handle12749709

    PubMed  Google Scholar 

  • PM Busse OK Harling MR Palmer WS Kiger SuffixIII J Kaplan I Kaplan CF Chuang JT Goorly KJ Riley TH Newton GA Santa-Cruz X-Q Lu RG Zamenhof (2003) ArticleTitleA critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease J Neurooncol 62 111–121 Occurrence Handle10.1023/A:1023249224364 Occurrence Handle12749707

    Article  PubMed  Google Scholar 

  • AD Chanana J Capala M Chadha JA Coderre AZ Diaz EH Elowitz J Iwai DD Joel HB Liu R Ma N Pendzick NS Peress MS Shady DN Slatkin GW Tyson L Wielopolski (1999) ArticleTitleBoron neutron capture therapy for glioblastoma multiforme: interim results from the Phase I/II dose-escalation studies Neurosurg 44 1182–1192 Occurrence Handle10.1097/00006123-199906000-00013

    Article  Google Scholar 

  • W Sauerwein R Moss K Hideghety F Stecher-Rasmusen M Vries Particlede H-J Reulen C Gvtz F Paquis K Grochulla K Haselsberger J Wolbers J Rassow JP Pignol P Watkins C Vroegindeweij K Ravensberg S Garbe OD Wiestler B Turowski F Zanella D Trow A Siefert R Huiskamp H Frankhauser D Gabel (1999) Status report on the European clinical trial of BNCT at Petten MF Hawthorne K Shelly RJ. Wiersema (Eds) Frontiers in Neutron Capture Therapy. Plenum Press New York

    Google Scholar 

  • P Busse R Zamenhof H Madoc-Jones G Solares S Kiger K Riley C Chuang G Rogers O Harling (1997) Clinical follow-up of patients with melanoma of the extremity treated in a phase I boron neutron capture therapy protocol B Larsson J Crawford R. Weinreich (Eds) Advances in Neutron Capture Therapy: Vol. 1,Medicine and Physics. Elsevier Science B.V. Amsterdam 60–64

    Google Scholar 

  • T Yamamoto A Matsumura K Nakai Y Shibata K Endo F Sakurai T Kishi H Kumada K Yamamoto Y Torii (2004) ArticleTitleCurrent clinical results of the Tsukuba BNCT trial Appl Radiat Isotopes 61 1089–1093 Occurrence Handle10.1016/j.apradiso.2004.05.010

    Article  Google Scholar 

  • RF Schinazi NM Goudgaon G Fulcrand Y El Kattan Z Lesnikowski GV Ullas J Moravek DC Liotta (1994) ArticleTitleCellular pharmacology and biological activity of 5-carboranyl-2′-deoxyuridine Int J Rad Oncol Biol Phys 28 1113–1120

    Google Scholar 

  • SJ Hurwitz A Eleuteri J Wright J Moravek RF Schinazi (2004) ArticleTitleCellular pharmacology of d and L-enantiomers of 5-carboranyl-2′-deoxyuridine (CDU) Boron delivery agents of BNCT Nucleosides Nucleotides Nucleic Acids 23 291–306 Occurrence Handle10.1081/NCN-120027836 Occurrence Handle15043155

    Article  PubMed  Google Scholar 

  • RF Schinazi SJ Hurwitz I Liberman AS Juodawlkis P Tharnish J Shi DC Liotta JA Coderre J Olson (2000) ArticleTitleTreatment of 9L rat brain tumors with β-5-o-carboranyl-2′-deoxyuridine neutron capture therapy Clin Cancer Res 6 725–730 Occurrence Handle10690559

    PubMed  Google Scholar 

  • AJ Lunato J Wang JE Woollard AKM Anisuzzaman W Ji F-G Rong S Ikeda AH Soloway S Eriksson DH Ives TE Blue W Tjarks (1999) ArticleTitleSynthesis of 5-(carboranylalkylmercapto)-2′-deoxyuridines and their evaluation as substrates for human thymidine kinases 1 and 2 J Med Chem 42 3378–3379 Occurrence Handle10.1021/jm990125i Occurrence Handle10464024

    Article  PubMed  Google Scholar 

  • I Gay DR Lorey RF Schinazi GH Morrison S Chandra (2001) ArticleTitleDynamic SIMS ion microscopy imaging of intracellular boron accumulation from carboranyl nucleosides in glioma cells Anticancer Res 21 2369–2376 Occurrence Handle11724295

    PubMed  Google Scholar 

  • X Zha WA Ausserer GH Morrison (1992) ArticleTitleQuantitative imaging of a therapeutic drug Na2B12H11SH at subcellular resolution in tissue cultures using ion microscopy Cancer Res 52 5219–5222 Occurrence Handle1394124

    PubMed  Google Scholar 

  • S Chandra DR Lorey SuffixII SL Lessig DR Smith GH Morrison (1977) Quantitative imaging of boron from BPA and BSH in glioblastoma cells with ion microscopy B Larsson J Crawford R Weinreich (Eds) Advances in Neutron Capture Therapy: Vol.2 Chemistry and Biology. Elsevier Amsterdam 315–320

    Google Scholar 

  • VR Jarugula RF Schinazi G Fulcrand-El Kattan DC Liotta FD Boudinot (1994) ArticleTitlePharmacokinetics of 5-carboranyl-2′-deoxyuridine in rats J Pharm Sci 83 1697–1699 Occurrence Handle7891296

    PubMed  Google Scholar 

  • RC Urtasan JD Chapman JA Raleigh AJ Franco CJ Koch (1986) ArticleTitleBinding of 3H-misonidazole in solid tumors as a measure of tumor hypoxia Int J Radiat Oncol Biol Phys 12 1263–1267

    Google Scholar 

  • J Folkman K Watson D Ingber D Hanahan (1989) ArticleTitleInduction of angiogenesis during transition from hyperplasia to neoplasia Lett Nature 339 58–61 Occurrence Handle10.1038/339058a0

    Article  Google Scholar 

  • SM Evans SM Hahn DP Magarelli CJ Koch (2001) ArticleTitleHypoxic Heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation Am J Clin Oncol 24 467–472 Occurrence Handle10.1097/00000421-200110000-00011 Occurrence Handle11586098

    Article  PubMed  Google Scholar 

  • PK Sallinen SL Sallinen PT Helen IS Rantala E Rautiainen HJ Helin H Kalimo HK Haapasalo (2000) ArticleTitleGrading of diffusely infiltrating astrocytomas by quantitative histopathology, cell proliferation and image cytometric DNA analysis. Comparison of 133 tumours in the context of the WHO 1979 and WHO 1993 grading schemes Neuropathol Appl Neurobiol 26 319–331 Occurrence Handle10.1046/j.1365-2990.2000.00240.x Occurrence Handle10931365

    Article  PubMed  Google Scholar 

  • RF Barth W Yang AS Al-Madhoun J Johnsamuel Y Byun S Chandra DR Smith W Tzarks S Eriksson (2004) ArticleTitleBoron containing nucleosides as potential delivery agents for neurton capture therapy of brain tumors Cancer Res 64 6287–6295 Occurrence Handle15342417

    PubMed  Google Scholar 

  • M Dahlstrom J Capala P Lindstrom A Wasteson A Lindstrom (2004) ArticleTitleAccumulation of boron in human malignant glioma cells in vitro is cell cycle dependent J Neuro Oncol 68 199–205 Occurrence Handle10.1023/B:NEON.0000033489.54011.6b

    Article  Google Scholar 

  • MH Fox RA Read JS Bedford (1987) ArticleTitleComparison of synchronized Chinese hamster ovary cells obtained by mitotic shake-off, hydroxyurea, aphidicolin, or cethotrexate Cytometry 8 315–320 Occurrence Handle10.1002/cyto.990080312 Occurrence Handle3109858

    Article  PubMed  Google Scholar 

  • DT Hung TF Jamison SL Schreiber (1996) ArticleTitleUnderstanding and controlling the cell cycle with natural products Chem Biol 1006 633–639

    Google Scholar 

  • A Krishan (1975) ArticleTitleRapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining J Cell Biol 66 188–193 Occurrence Handle10.1083/jcb.66.1.188 Occurrence Handle49354

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nuclear Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    Casey Moore & Chris Wang

  2. Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Medical Research –,151-H, 1670 Clairmont Road, Decatur, Georgia, 30033, USA

    Brenda I. Hernández-Santiago, Selwyn J. Hurwitz, Chalet Tan & Raymond F. Schinazi

Authors
  1. Casey Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brenda I. Hernández-Santiago
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Selwyn J. Hurwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chalet Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chris Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Raymond F. Schinazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raymond F. Schinazi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moore, C., Hernández-Santiago, B.I., Hurwitz, S.J. et al. The Boron–Neutron Capture Agent β-d-5-o-Carboranyl-2′-deoxyuridine Accumulates Preferentially in Dividing Brain Tumor Cells. J Neurooncol 74, 275–280 (2005). https://doi.org/10.1007/s11060-004-8323-y

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-004-8323-y

Keywords

Search

Navigation