Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects

Clinical Cancer Research - Tập 11 Số 11 - Trang 3987-4002 - 2005
Rolf F. Barth1, Jeffrey A. Coderre2, M. Graça H. Vicente3, Thomas E. Blue4
11Department of Pathology and
23Department of Nuclear Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; and
34Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana
42Nuclear Engineering Program, The Ohio State University, Columbus, Ohio;

Tóm tắt

Abstract Background: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer α particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. Boron Delivery Agents: Two boron drugs have been used clinically, sodium borocaptate (Na2B12H11SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations (∼20 μg/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boron-containing amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. Clinical Trials: Current or recently completed clinical trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of “debulking” surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v. have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established. Conclusions: Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.

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Tài liệu tham khảo

Berger MS. Malignant astrocytomas: surgical aspects. Semin Oncol 1994;21:172–85.

Gutin PH, Posner JB. Neuro-oncology: diagnosis and management of cerebral gliomas—past, present, and future. Neurosurgery 2000;47:1–8.

Parney IF, Chang SM. Current chemotherapy for glioblastoma. In: Market J, DeVita VT, Rosenberg SA, Hellman S, editors. Glioblastoma multiforme. 1st ed. Sudbury: Jones and Bartlett Publishers; 2005. p. 161–77.

Paul DB, Kruse CA. Immunologic approaches to therapy for brain tumors. Curr Neurol Neurosci Rep 2001;1:238–44.

Rainov NG. Gene therapy for human malignant brain tumors. In: Market J, De Vita VT, Rosenberg SA, Hellman S, editors. Glioblastoma multiforme. 1st ed. Sudbury: Jones and Bartlett Publishers; 2005. p. 249–65.

Curran WJ, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three radiation oncology group malignant glioma trials. J Natl Cancer Inst 1993;85:704–10.

Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001;95:190–8.

Hentschel SJ, Lang FF. Current surgical management of glioblastoma. In: Market J, DeVita VT, Rosenberg SA, Hellman S, editors. Glioblastoma multiforme. 1st ed. Sudbury: Jones and Bartlett Publishers; 2005. p. 108–30.

Laws ER, Shaffrey ME. The inherent invasiveness of cerebral gliomas: implications for clinical management. Int J Dev Neurosci 1999;17:413–20.

Halperin EC, Burger PC, Bullard DE. The fallacy of the localized supratentorial malignant glioma. Int J Radiat Oncol Biol Phys 1988;15:505–9.

Kaczarek E, Zapf S, Bouterfa H, Tonn JC, Westphal M, Giese A. Dissecting glioma invasion: interrelation of adhesion, migration and intercellular contacts determine the invasive phenotype. Int J Dev Neurosci 1999;17:625–41.

Huang S, Prabhu S, Sawaya R. Molecular and biological determinants of invasiveness and angiogenesis in central nervous system tumors. In: Zhang W, Fuller GN, editors. Genomic and molecular neuro-oncology. Sudbury (MA): Jones and Bartlette Publishers; 2004. p. 97–118.

Parney IF, Hao C, Petruk K. Glioma immunology and immunotherapy. Neurosurgery 2000;46:778–92.

Ware ML, Berger MS, Binder DK. Molecular biology of glioma tumorigenesis. Histol Histopathol 2003;18:207–16.

Barth RF. A critical assessment of boron neutron capture therapy: an overview. J Neurooncol 2003;62:1–5.

Busse PM, Harling OK, Palmer MR, et al. A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease. J Neurooncol 2003;62:111–21.

Mishima Y. Selective thermal neutron capture therapy of cancer cells using their specific metabolic activities—melanoma as prototype. In: Mishima Y, editor. Cancer neutron capture therapy. New York: Plenum Press; 1996. p. 1–26.

Coderre JA, Turcotte JC, Riley KJ, Binns PJ, Harling OK, Kiger III WS. Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation. Technol Cancer Res Treat 2003;2:1–21.

Sauerwein W, Moss R, Wittig A, editors. Research and development in neutron capture therapy. Bologna (Italy): Monduzzi Editore S.p.A., International Proceedings Division; 2002.

Coderre JA, Rivard MJ, Patel H, Zamenhof RG. (eds)Topics in Neutron CaptureTherapy: Proceedings of the 11th World Congress on Neutron Capture Therapy. Applied Radiation Isotopes, Volume 61, November 2004.

Coderre JA, Morris GM. The radiation biology of boron neutron capture therapy. Radiat Res 1999;151:1–18.

Morris GM, Coderre JA, Hopewell JW, et al. Response of the central nervous system to boron neutron capture irradiation: evaluation using rat spinal cord model. Radiother Oncol 1994;32:249–55.

Morris GM, Coderre JA, Hopewell JW, Micca PL, Rezvani M. Response of rat skin to boron neutron capture therapy with p-boronophenylalanine or borocaptate sodium. Radiother Oncol 1994;32:144–53.

Gupta N, Gahbauer RA, Blue TE, Albertson B. Common challenges and problems in clinical trials of boron neutron capture therapy of brain tumors. J Neurooncol 2003;62:197–210.

Nigg DW. Computational dosimetry and treatment planning considerations for neutron capture therapy. J Neurooncol 2003;62:75–86.

Fukuda H, Hiratsuka J, Honda C, et al. Boron neutron capture therapy of malignant melanoma using 10B-paraboronophenylalanine with special reference to evaluation of radiation dose and damage to the skin. Radiat Res 1994;138:435–42.

Coderre JA, Elowitz EH, Chadha M, et al. Boron neutron capture therapy for glioblastoma multiforme using p-boronophenylalanine and epithermal neutrons: trial design and early clinical results. J Neurooncol 1997;33:141–52.

Elowitz EH, Bergland RM, Coderre JA, Joel DD, Chadha M, Chanana AD. Biodistribution of p-boronophenylalanine in patients with glioblastoma multiforme for use in boron neutron capture therapy. Neurosurgery 1998;42:463–9.

Coderre JA, Makar MS, Micca PL, et al. Derivations of relative biological effectiveness for the high-LET radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo. Int J Radiat Oncol Biol Phys 1993;27:1121–9.

Barth RF, Yang W, Rotaru JH, et al. Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption. Cancer Res 1997;57:1129–36.

Barth RF, Yang W, Rotaru JH, et al. Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine. Int J Radiat Oncol Biol Phys 2000;47:209–18.

Miyatake S-I, Kajimoto Y, Kawabata S, et al. Clinical results of modified BNCT for malignant glioma using two boron. Abstracts of the 11th World Congress on Neutron Capture Therapy; 2004 Oct 11–15; Boston, MA. p. 61.

Barth RF, Grecula JC, Yang W, et al. Combination of boron neutron capture therapy and external beam X-irradiation for the treatment of brain tumors. Int J Radiat Oncol Biol Phys 2004;58:267–77.

Farr LE, Sweet WH, Robertson JS, et al. Neutron capture therapy with boron in the treatment of glioblastoma multiforme. Am J Roentgenol 1954;71:279–91.

Godwin JT, Farr LE, Sweet WH, Robertson JS. Pathological study of eight patients with glioblastoma multiforme treated by neutron-capture therapy using boron 10. Cancer 1955;8:601–15.

Snyder HR, Reedy AJ, Lennarz WJ. Synthesis of aromatic boronic acids, aldehydo boronic acids and a boronic acid analog of tyrosine. J Am Chem Soc 1958;80:835–8.

Soloway AH, Hatanaka H, Davis MA. Penetration of brain and brain tumor. VII. Tumor-binding sulfhydryl boron compounds. J Med Chem 1967;10:714.

Hawthorne MF. The role of chemistry in the development of boron neutron capture therapy of cancer. Angew Chem Int Ed Engl 1993;32:950–84.

Morin C. The chemistry of boron analogues of biomolecules. Tetrahedron 1994;50:12521–69.

Soloway AH, Tjarks W, Barnum BA, et al. The chemistry of neutron capture therapy. Chem Rev 1998;98:1515–62.

Hawthorne MF, Lee MW. A critical assessment of boron target compounds for boron neutron capture therapy. J Neurooncol 2003;62:33–45.

Olsson P, Gedda L, Goike H, et al. Uptake of a boronated epidermal growth factor-dextran conjugate in CHO xenografts with and without human EGF-receptor expression. Anticancer Drug Des 1998;13:279–89.

Gabel D, Foster S, Fairchild RG. The Monte Carlo simulation of the biological effect of the 10B(n,α)7L reaction in cells and tissue and its implication for boron neutron capture therapy. Radiat Res 1987;111:14–25.

Srivastava RR, Singhaus RR, Kabalka GW. 4-Dihydroxyborylphenyl analogues of 1-aminocyclobutanecarboxylic acids: potential boron neutron capture therapy agents. J Org Chem 1999;64:8495–500.

Das BC, Das S, Li G, Bao W, Kabalka GW. Synthesis of a water soluble carborane containing amino acid as a potential therapeutic agent. Synlett 2001;9:1419–20.

Kabalka GW, Yao M-L. Synthesis of a novel boronated 1-amino-cyclobutane carboxylic acid as a potential boron neutron capture therapy agent. Appl Organomet Chem 2003;17:398–402.

Diaz S, Gonzalez A, De Riancho SG, Rodriguez A. Boron complexes of S-trityl-l-cysteine and S-tritylglutathione. J Organomet Chem 2000;610:25–30.

Lindström P, Naeslund C, Sjöberg S. Enantioselective synthesis and absolute configurations of the enantiomers of o-carboranylalanine. Tetrahedron Lett 2000;41:751–4.

Masunaga S-I, Ono K, Kirihata M, et al. Potential of α-amino alcohol p-boronophenylalaninol as a boron carrier in boron neutron capture therapy, regarding its enantiomers. J Cancer Res Clin Oncol 2003;129:21–8.

Diaz A, Stelzer K, Laramore G, Wiersema R. Pharmacology studies of Na210B10H10 (GB-10) in human tumor patients. In: M.W. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. p. 993–9 .

Hawthorne MF, Feakes DA, Shelly K. Recent results with liposomes as boron delivery vehicles from boron neutron capture therapy. In: Mishima Y, editor. Cancer neutron capture therapy. New York: Plenum Press; 1996. p. 27–36.

Feakes DA, Waller RC, Hathaway DK, Morton VS. Synthesis and in vivo murine evaluation of Na4[1-(1′-B10H9)-6-SHB10H8] as a potential agent for boron neutron capture therapy. Proc Natl Acad Sci U S A 1999;96:6406–10.

Takagaki M, Powell W, Sood A, et al. Boronated dipeptide borotrimethylglycylphenylalanine as a potential boron carrier in boron neutron capture therapy for malignant brain tumors. Radiat Res 2001;156:118–22.

Wakamiya T, Yamashita T, Fujii T, Yamaguchi Y, Nakano T, Kirihata M. Synthesis of 4-boronophenylalanine-containing peptides for boron neutron capture therapy of cancer cells. J Pept Sci 1999;36:209–12.

Lesnikowski ZJ, Schinazi RF. Boron containing oligonucleotides. Nucleosides Nucleotides 1998;17:635–47.

Lesnikowski ZJ, Shi J, Schinazi RF. Nucleic acids and nucleosides containing carboranes. J Organomet Chem 1999;581:156–69.

Lunato AJ, Wang J, Woollard JE, et al. Synthesis of 5-(carboranylalkylmercapto)-2′-deoxyuridines and 3-(carboranylalkyl)thymidines and their evaluation as substrates for human thymidine kinases 1 and 2. J Med Chem 1999;42:3378–89.

Al-Madhoun AS, Johnsamuel J, Yan J, et al. Synthesis of a small library of 3-(carboranylalkyl)thymidines and their biological evaluation as substrates for human thymidine kinases 1 and 2. J Med Chem 2002;45:4018–28.

Al-Madhoun AS, Johnsamuel J, Barth RF, Tjarks W, Eriksson S. Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy. Cancer Res 2004;64:6280–6.

Barth RF, Yang W, Al-Madhoun AS, et al. Boron containing nucleosides as potential delivery agents for neutron capture therapy of brain tumors. Cancer Res 2004;64:6287–95.

Sjöberg S, Carlsson J, Ghaneolhosseini H, et al. Chemistry and biology of some low molecular weight boron compounds for boron neutron capture therapy. J Neurooncol 1997;33:41–52.

Tietze LF, Griesbach U, Bothe U, Nakamura H, Yamamoto Y. Novel carboranes with a DNA binding unit for the treatment of cancer by boron neutron capture therapy. Chembiochem 2002;3:219–25.

Bateman SA, Kelly DP, Martin RF, White JM. DNA binding compounds. VII. Synthesis, characterization and DNA binding capacity of 1,2-dicarba-closo-dodecaborane bibenzimidazoles related to the DNA minor groove binder Hoechst 33258. Aust J Chem 1999;52:291–301.

Woodhouse SL, Rendina LM. Synthesis and DNA-binding properties of dinuclear platinum(II)-amine complexes of 1,7-dicarba-closo-dodecaborane(12). Chem Commun 2001;2464–5.

Cai J, Soloway AH, Barth RF, et al. Boron-containing polyamines as DNA-targeting agents for neutron capture therapy of brain tumors: synthesis and biological evaluation. J Med Chem 1997;40:3887–96.

Zhuo J-C, Cai J, Soloway AH, et al. Synthesis and biological evaluation of boron-containing polyamines as potential agents for neutron capture therapy of brain tumors. J Med Chem 1999;42:1281–92.

Martin B, Posseme F, Le Barbier C, et al. N-benzylpolyamines as vectors of boron and fluorine for cancer therapy and imaging: synthesis and biological evaluation. J Med Chem 2001;44:3653–64.

El-Zaria ME, Doerfler U, Gabel D. Synthesis of [(aminoalkylamine)-N-aminoalkyl]azanonaborane(11) derivatives for boron neutron capture therapy. J Med Chem 2002;45:5817–9.

Nakanishi A, Guan L, Kane RR, Kasamatsu H, Hawthorne MF. Toward a cancer therapy with boron-rich oligomeric phosphate diesters that target the cell nucleus. Proc Natl Acad Sci U S A 1999;96:238–41.

Maderna A, Huertas R, Hawthorne MF, Luguya R, Vicente MGH. Synthesis of a porphyrin-labelled carboranyl phosphate diester: a potential new drug for boron neutron capture therapy of Cancer. Chem Commun (Camb) 2002;1784-5.

Vicente MGH. Porphyrin-based sensitizers in the detection and treatment of cancer: recent progress. Curr Med Chem Anti-Canc Agents 2001;1:175–94.

Bregadze VI, Sivaev IB, Gabel D, Wöhrle D. Polyhedral boron derivatives of porphyrins and phthalocyanines. J Porphyrins Phthalocyanines 2001;5:767–81.

Evstigneeva RP, Zaitsev AV, Luzgina VN, Ol'shevskaya VA, Shtil AA. Carboranylporphyrins for boron neutron capture therapy of cancer. Curr Med Chem Anti-Canc Agents 2003;3:383–92.

Vicente MGH, Wickramasighe A, Nurco DJ, et al. Syntheses, toxicity and biodistribution of two 5,15-di[3,5-(nido-carboranyl-methyl)phenyl]porphyrin in EMT-6 tumor bearing mice. Bioorg Med Chem 2003;11:3101–8.

Fronczek FR, Vicente MGH. Synthesis and cellular studies of an octa-anionic 5,10,15,20-tetra[3,5(nido-carboranylmethyl)phenyl]porphyrin (H2OCP) for application in BNCT. Bioorg Med Chem 2005;13:1633–40.

Miura M, Joel DD, Smilowitz HM, et al. Biodistribution of copper carboranyltetraphenylporphyrins in rodents bearing an isogeneic or human neoplasm. J Neurooncol 2001;52:111–7.

Miura M, Morris GM, Micca PL, et al. Boron neutron capture therapy of a murine mammary carcinoma using a lipophilic carboranyltetraphenylporphyrin. Radiat Res 2001;155:603–10.

Fabris C, Jori G, Giuntini F, Roncucci G. Photosensitizing properties of a boronated phthalocyanine: studies at the molecular and cellular level. J Photochem Photobiol B 2001;64:1–7.

Rosenthal MA, Kavar B, Uren S, Kaye AH. Promising survival in patients with high-grade gliomas following therapy with a novel boronated porphyrin. J Clin Neurosci 2003;10:425–7.

Rosenthal MA, Kavar B, Hill JS, et al. Phase I and pharmacokinetic study of photodynamic therapy for high-grade gliomas using a novel boronated porphyrin. J Clin Oncol 2001;19:519–24.

Hill JS, Kahl SB, Stylli SS, Nakamura Y, Koo M-S, Kaye AH. Selective tumor kill of cerebral glioma by photodynamic therapy using a boronated porphyrin photosensitizer. Proc Natl Acad Sci U S A 1995;92:12126–30.

Lauceri R, Purrello R, Shetty SJ, Vicente MGH. Interactions of anionic carboranylated porphyrins with DNA. J Am Chem Soc 2001;123:5835–6.

Vicente MGH, Nurco DJ, Shetty SJ, et al. Synthesis, dark toxicity and induction of in vitro DNA photodamage by a tetra(4-nido-carboranylphenyl)porphyrin. J Photochem Photobiol B 2002;68:123–32.

Ghaneolhosseini H, Tjarks W, Sjoberg S. Synthesis of novel boronated acridines and spermidines as possible agents for BNCT. Tetrahedron 1998;54:3877–84.

Gedda L, Silvander M, Sjoberg S, Tjarks W, Carlsson J. Cytotoxicity and subcellular localization of boronated phenanthridinium analogs. Anticancer Drug Des 1997;12:671–85.

Gedda L, Ghaneolhosseini H, Nilsson P, et al. The influence of lipophilicity on binding of boronated DNA-intercalating compounds in human glioma spheroids. Anticancer Drug Des 2000;15:277–86.

Giovenzana GB, Lay L, Monti D, Palmisano G, Panza L. Synthesis of carboranyl derivatives of alkynyl glycosides as potential BNCT agents. Tetrahedron 1999;55:14123–36.

Tietze LF, Bothe U, Griesbach U, et al. Ortho-carboranyl glycosides for the treatment of cancer by boron neutron capture therapy. Bioorg Med Chem 2001;9:1747–52.

Orlova AV, Zinin AI, Malysheva NN, Kononov LO, Sivaev IB, Bregadze VI. Conjugates of polyhedral boron compounds with carbohydrates. 1. New approach to the design of selective agents for boron neutron capture therapy of cancer. Russian Chem Bull 2003;52:2766–8.

Tietze LF, Bothe U. Ortho-carboranyl glycosides of glucose, mannose, maltose and lactose for cancer treatment by boron neutron-capture therapy. Chem Eur J 1998;4:1179–83.

Raddatz S, Marcello M, Kliem H-C, et al. Synthesis of new boron-rich building blocks for boron neutron capture therapy or energy-filtering transmission electron microscopy. Chembiochem 2004;5:474–82.

Tietze LF, Griesbach U, Schuberth I, Bothe U, Marra A, Dondoni A. Novel carboranyl C-glycosides for the treatment of cancer by boron neutron capture therapy. Chem Eur J 2003;9:1296–302.

Basak P, Lowary TL. Synthesis of conjugates of l-fucose and ortho-carborane as potential agents for boron neutron capture therapy. Can J Chem 2002;80:943–8.

Endo Y, Iijima T, Yamakoshi Y, Kubo A, Itai A. Structure-activity study of estrogenic agonists bearing dicarba-closo-dodecaborane. Effect of geometry and separation distance of hydroxyl groups at the ends of molecules. Bioorg Med Chem Lett 1999;9:3313–8.

Lee J-D, Lee C-H, Nakamura H, Ko J, Kang SO. A convenient synthesis of the novel carboranyl-substituted tetrahydroisoquinolines: application to the biologically active agent for BNCT. Tetrahedron Lett 2002;43:5483–6.

Valliant JF, Schaffer P, Stephenson KA, Britten JF. Synthesis of boroxifen, a nido-carborane analogue of tamoxifen. J Org Chem 2002;67:383–7.

Feakes DA, Spinler JK, Harris FR. Synthesis of boron-containing cholesterol derivatives for incorporation into unilamellar liposomes and evaluation as potential agents for BNCT. Tetrahedron 1999;55:11177–86.

Endo Y, Iijima T, Yamakoshi Y, et al. Potent estrogen agonists based on carborane as a hydrophobic skeletal structure: a new medicinal application of boron clusters. Chem Biol 2001;8:341–55.

Tjarks W, Barth RF, Rotaru JH, et al. In vivo evaluation of phosphorous-containing derivatives of dodecahydro-closo-dodecaborate for boron neutron capture therapy of gliomas and sarcomas. Anticancer Res 2001;21:841–6.

Adams DM, Ji W, Barth RF, Tjarks W. Comparative in vitro evaluation of dequalinium B, a new boron carrier for neutron capture therapy (NCT). Anticancer Res 2000;20:3395–402.

Zakharkin LI, Ol'shevskaya VA, Spryshkova RA, Grigor'eva EY, Ryabkova VI, Borisov GI. Synthesis of bis(dialkylaminomethyl)-o- and m-carboranes and study of these compounds as potential preparations for boron neutron capture therapy. Pharm Chem J 2000;34:301–4.

Barth RF, Adams DM, Soloway AH, Alam F, Darby MV. Boronated starburst dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy. Bioconjug Chem 1994;5:58–66.

Liu L, Barth RF, Adams DM, Soloway AH, Reisfeld RA. Critical evaluation of bispecific antibodies as targeting agents for boron neutron capture therapy of brain tumors. Anticancer Res 1996;16:2581–8.

Liu L, Barth RF, Adams D, Soloway AH, Reisfeld RA. Bispecific antibodies as targeting agents for boron neutron capture therapy of brain tumors. J Hematother 1995;4:477–83.

Novick S, Quastel MR, Marcus S, et al. Linkage of boronated polylysine to glycoside moieties of polyclonal antibody; Boronated antibodies as potential delivery agents for neutron capture therapy. Nucl Med Biol 2002;29:93–101.

Wu G, Barth RF, Yang W, et al. Site-specific conjugation of boron containing dendrimers to anti-EGF receptor monoclonal antibody cetuximab (IMC-C225) and its evaluation as a potential delivery agent for neutron capture therapy. Bioconjug Chem 2004;15:185–94.

Fallot T, Magdelena TH, Mady E, et al. A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas. Neurosurgery 1996;39:478–83.

Carlsson J, Gedda L, Grönvik C, et al. Strategy for boron neutron capture therapy against tumor cells with over-expression of the epidermal growth factor receptor. Int J Radiat Oncol Biol Phys 1994;30:105–15.

Capala J, Barth RF, Bendayan M, et al. Boronated epidermal growth factor as a potential targeting agent for boron neutron capture therapy of brain tumors. Bioconjug Chem 1996;7:7–15.

Sauter G, Maeda T, Waldman FM, Davis RL, Feuerstein BG. Patterns of epidermal growth factor receptor amplification in malignant gliomas. Am J Pathol 1996;148:1047–53.

Schwechheimer K, Huang S, Cavenee WK. EGFR gene amplification-rearrangement in human glioblastoma. Int J Cancer 1995;62:145–8.

Backer MV, Backer JM. Targeting endothelial cells overexpressing VEGFR-2: selective toxicity of Shinga-like toxin-VEGF fusion proteins. Bioconjug Chem 2001;12:1066–73.

Feakes DA, Shelly K, Hawthorne M. Selective boron delivery to murine tumors by lipophilic species incorporated in the membranes of unilamellar liposomes. Proc Natl Acad Sci U S A 1995;92:1367–70.

Carlsson J, Kullberg EB, Capala J, Sjöberg S, Edwards K, Gedda L. Ligand liposomes and boron neutron capture therapy. J Neurooncol 2003;62:47–59.

Pardridge WM. Drug delivery to the brain. J Cereb Blood Flow Metab 1997;17:713–31.

Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002;20:1–13S.

FDA approves Erbitux for advanced colon cancer. Oncol News Int 13:2004, p1.

Wikstrand CJ, Cokgor I, Sampson JH, Bigner DD. Monoclonal antibody therapy of human gliomas: current status and future approaches. Cancer Metastasis Rev 1999;18:451–64.

Barth RF, Yang W, Adams DM, et al. Molecular targeting of the epidermal growth factor receptor for neutron capture therapy of gliomas. Cancer Res 2002;62:3159–66.

Yang W, Barth RF, Adams DM, et al. Convection enhanced delivery of boronated epidermal growth factor for molecular targeting of EGFR positive gliomas. Cancer Res 2002;62:6552–8.

Yang W, Barth RF, Ciesielski MJ, et al. Development of a syngeneic rat brain tumor model expressing EGFRvIII and its use for molecular targeting studies with monoclonal antibody L8A4. Clin Cancer Res 2005;11:341–50.

Barth RF, Wu G, Yang W, et al. Neutron capture therapy of epidermal growth factor positive gliomas using boronated cetuximab (IMC-C225) as a delivery agent. Appl Radiat Isot 2004;61:899–903.

Yang W, Barth RF, Wu G, et al. Boronated epidermal growth factor as a delivery agent for neutron capture therapy of EGFR positive gliomas. Appl Radiat Isot 2004;61:981–5.

Barth RF, Yang W, Bartus RT, et al. Neutron capture therapy of intracerebral melanoma: enhanced survival and cure following blood-brain barrier opening to improve delivery of boronophenylalanine. Int J Radiat Oncol Biol Phys 2002;52:858–68.

Barth RF, Yang W, Moeschberger ML, Goodman JH, Bartus RT. Enhanced delivery of boronophenylalanine for neutron capture therapy of brain tumors using the bradykinin analogue, Cereport™ (RMP7). Neurosurgery 1999;44:350–9.

Yang W, Barth RF, Wu G, et al. Development of a syngeneic rat brain tumor model expressing EGFRvIII and its use for molecular targeting studies with monoclonal antibody L8A4. Clin Cancer Res 2005;11:341–50.

Kawabata S, Barth RF, Yang W, Wu G, Wickramsinghe A, Vicente G. Biodistribution of two carboranyl porphyrins, ZnDCP and H2DCP, following systemic and convection enhanced delivery to brain tumor bearing animals. Abstracts of the 11th World Congress on Neutron Capture Therapy; 2004 Oct 11–15; Boston, MA. p. 21.

Harling O, Riley K. Fission reactor neutron sources for neutron capture therapy—a critical review. J Neurooncol 2003;2:7–17.

Harling O, Riley K, Newton T, et al. The fission converter-based epithermal neutron irradiation facility at the Massachusetts Institute of Technology reactor. Nucl Sci Eng 2002;140:223–40.

Capala J, H.-Stenstam B, Sköld K, et al. Boron neutron capture therapy for glioblastoma multiforme: clinical studies in Sweden. J Neurooncol 2003;62:135–44.

Joensuu H, Kankaanranta L, Seppälä T, et al. Boron neutron capture therapy of brain tumors: clinical trials at the Finnish Facility using boronophenylalanine. J Neurooncol 2003;62:123–34.

Moss RL, Stecher-Rasmussen F, Ravensberg K, Constantine G, Watkins P. Design, construction and installation of an epithermal neutron beam for BNCT at the High Flux Reactor Petten. In: Allen BJ, Moore DE, Harrinston BV editors. Progress in neutron capture therapy for cancer. New York: Plenum Press; 1992. p. 63–6.

Marek M, Viererbl M, Burian J, Jansky B. Determination of the geometric and spectral characteristics of BNCT beam (neutron and γ-ray). In: Hawthorne MF, Shelly K, Wiersema RJ, editors. Neutron capture therapy. Vol. I. New York: Kluwer Academic/Plenum Publishers; 2001. p. 381–9.

Kobayashi T, Sakurai Y, Kanda K, Fujita Y, Ono K. The remodeling and basic characteristics of the heavy water neutron irradiation facility of the Kyoto University Research Reactor, mainly for neutron capture therapy. Nucl Technol 2000;131:354–78.

Yamamoto K, Kumada H, Torii Y, et al. Characteristics of neutron beams for BNCT. Proceedings of the 9th Symposium on Neutron Capture Therapy; 2000 Oct 2–6; Osaka, Japan. p. 243–44.

Blaumann HR, Larrieu OC, Longhino JM, Albornoz AF. NCT facility development and beam characterisation at the RA-6 Reactor. In: Hawthorne MF, Shelly K, Wiersema RJ, editors. Frontiers in neutron capture therapy. Vol. I. New York: Kluwer Academic/Plenum Publishers; 2001. p. 313–7.

Agosteo S, Foglio Para A, Gambarini G, et al. Design of neutron beams for boron neutron capture therapy in a fast reactor. IAEA Technical Committee Meeting about the Current Issues Relating to Neutron Capture Therapy; Vienna, Austria; 1999 Jun 14–18.

Fairchild RG, Kalef-Ezra JK, Saraf SK, et al. Installation and testing of an optimized epithermal neutron beam at the Brookhaven Medical Research Reactor (BMRR). Proceedings of the Workshop on Neutron Beam Design, Development and Performance for Neutron Capture Therapy; MIT, Cambridge, MA; 1989 Mar 29–31.

Hatanaka H. Boron neutron capture therapy for brain tumors. In: Karin ABMF, Laws E, editors. Glioma. Berlin: Springer-Verlag; 1991. p. 233–49.

Hatanaka H, Nakagawa Y. Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy. Int J Radiat Oncol Biol Phys 1994;28:1061–6.

Diaz AZ. Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a clinician's point of view. J Neurooncol 2003;62:101–9.

Riley K, Binns P, Harling O. Performance characteristics of the MIT fission converter based epithermal neutron beam. Phys Med Biol 2003;48:943–58.

Nigg D, et al. Initial neutronic performance assessment of an epithermal neutron beam for neutron capture therapy research at Washington State University. Research and development inneutron capture therapy. In: MW. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. pp. 135–9.

Beynon T, Forcey KS, Green S, Cruickshank G, James N. Status of the Birmingham accelerator based BNCT facility. In: M.W. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. p. 225–8.

Burlon A, Kreiner A,Valda A, et al. Optimization of a neutron production target and beam shaping assembly based on the 7Li(p.n)7 Be reaction. In: M.W.Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. p. 229–34.

Kononov O, Kononov V, Koroveynikov V, et al. Investigations of using near-threshold 7Li(p.n)7Be reaction for NCT based on in-phantomdose distribution. In: M.W. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. p. 241–6.

Blackburn B, Yanch J, Klinkowstein R. Development of a high-power water cooled beryllium target for use in accelerator-based boron neutron capture therapy. Med Phys 1998;10:1967–74.

Hawk A, Blue T, Woolard J, Gupta N. Effects of target thickness on neutron field quality for an ABNS. Research and development in neutron capture therapy. In: M.W. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. p. 253–57.

Sakurai Y, Kobayashi T, Ono K. Study on accelerator-base neutron irradiation field aiming for wider application in BNCT—Kspectrum shift and regional filtering. In: M.W. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. pp. 259–63

Giusti V, Esposito J. Neutronic feasibility study of an accelerator-based thermal neutron irradiation cavity. In: M.W. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. pp. 305–8.

Blue TE, Yanch JC. Accelerator-based epithermal neutron sources for boron neutron capture therapy of brain tumors. J Neurooncol 2003;62:19–31.

Starling WJ. RFI Linac for accelerator-based neutrons. Abstracts of the 11th World Congress on Neutron Capture Therapy; 2004 Oct 11–5; Boston, MA. p. 45.

Locher GL. Biological effects and therapeutic possibilities of neutrons. Am J Roentgenol Radium Ther 1936;36:1–13.

Asbury AK, Ojemann, Nielson SL, Sweet WH. Neuropathologic study of fourteen cases of malignant brain tumor treated by boron-10 slow neutron capture therapy. J Neuropathol Exp Neurol 1972;31:278–303.

Sweet WH. Practical problems in the past in the use of boron-slow neutron capture therapy in the treatment of glioblastoma multiforme. Proceedings of the First International Symposium on Neutron Capture Therapy; 1983 Oct 12–14. Brookhaven National Laboratory Reports 51730. p. 376–8.

Slatkin DN. A history of boron neutron capture therapy of brain tumours. Postulation of a brain radiation dose tolerance limit. Brain 1991;114:1609–29.

Nakagawa Y, Hatanaka H. Boron neutron capture therapy: clinical brain tumor studies. J Neurooncol 1997;33:105–15.

Nakagawa Y, Pooh K, Kobayashi T, et al. Clinical review of the Japanese experience with boron neutron capture therapy and a proposed strategy using epithermal neutron beams. J Neurooncol 2003;62:87–99.

Laramore GE, Wootton P, Livesey JC, et al. Boron neutron capture therapy: a mechanism for achieving a concomitant tumor boost in fast neutron radiotherapy. Int J Radiat Oncol Biol Phys 1994;28:1135–42.

Kageji T, Nakagawa Y, Kitamura K, Matsumoto K, Hatanaka H. Pharmacokinetics and boron uptake of BSH (Na2B12H11SH) in patients with intracranial tumors. J Neurooncol 1997;33:117–30.

Bergland R, Elowitz E, Coderre JA, Joel D, Chadha M. A phase 1 trial of intravenous boronophenylalanine-fructose complex in patients with glioblastoma multiforme. In: Mishima Y, editor. Cancer neutron capture therapy. New York: Plenum Press; 1996. p. 739–46.

Coderre JA, Chanana AD, Joel DD, et al. Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity. Radiat Res 1998;149:163–70.

Chanana AD, Capala J, Chadha M, et al. Boron neutron capture therapy for glioblastoma multiforme: interim results from the phase I/II dose-escalation studies. Neurosurgery 1999;44:1182–93.

Busse P, Zamenhof R, Harling O, et al. The Harvard-MIT BNCT program: overview of the clinical trials and translational research. In: Hawthorne MF, Shelly K, Wiersema RJ, editors. Frontiers in neutron capture therapy. Vol. 1. New York: Kluwer Academic/Plenum Publishers; 2001. p. 37–60.

Palmer MR, Goorley JT, Kiger WS, et al. Treatment planning and dosimetry for the Harvard-MIT phase I clinical trial of cranial neutron capture therapy. Int J Radiat Oncol Biol Phys 2002;53:1361–79.

Wittig A, Hideghety K, Paquis P, et al. Current clinical results of the EORTC-study 11961. In: Sauerwein W, Moss R Wittig A, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore; 2002. p. 1117–22.

Burian J, Marek M, Rataj J, et al. Report on the first patient group of the phase I BNCT trial at the LVR-15 reactor. In: Sauerwein W, Moss R Wittig A, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore; 2002. p. 1107–12.

Coderre JA, Hopewell JW, Turcotte JC, et al. Tolerance of normal human brain to boron neutron capture therapy. Appl Radiat Isot 2004;61:1084–7.

Flickinger JC, Kondziolka D, Lunsford LD, et al. Development of a model to predict permanent symptomatic postradiosurgery injury for arteriovenous malformation patients. Arteriovenous Malformation Radiosurgery Study Group. Int J Radiat Oncol Biol Phys 2000;46:1143–8.

Wittig A, Sauerwein WA, Coderre JA. Mechanisms of transport of p-borono-phenylalanine through the cell membrane in vitro. Radiat Res 2000;153:173–80.

Joel DD, Coderre JA, Micca PL, Nawrocky MM. Effect of dose and infusion time on the delivery of p-boronophenylalanine for neutron capture therapy. J Neurooncol 1999;41:213–21.

Morris GM, Micca PL, Nawrocky MM, Weissfloch LE, Coderre JA. Long-term infusions of p-boronophenylalanine for boron neutron capture therapy: evaluation using rat brain tumor and spinal cord models. Radiat Res 2002;158:743–52.

Smith DR, Chandra S, Coderre JA, Morrison GH. Ion microscopy imaging of 10B from p-boronophenylalanine in a brain tumor model for boron neutron capture therapy. Cancer Res 1996;56:4302–6.

Smith D, Chandra S, Barth R, Yang W, Joel D, Coderre J. Quantitative imaging and microlocalization of boron-10 in brain tumors and infiltrating tumor cells by SIMS ion microscopy: relevance to neutron capture therapy. Cancer Res 2001;61:8179–87.

Mishima Y, Ichihashi M, Hatta S, Honda C, Yamamura K, Nakagawa T. New thermal neutron capture therapy for malignant melanoma. Melanogenesis-seeking 10B molecular-melanoma cell interaction from in vitro to first clinical trial. Pigment Cell Res 1989;2:226–34.

Hiratsuka J, Kono, Mishima Y. RBEs of thermal neutron capture therapy and 10B(n,α)7Li reaction on melanoma-bearing hamsters. Pigment Cell Res 1989;2:352–5.

Tsuji M, Ichihashi M, Mishima Y. Selective affinity of 10B-paraboronophenylalanine-HCI to malignant melanoma for thermal neutron capture therapy. J Dermatol 1983;93:773–8.

Coderre JA, Glass JD, Fairchild RG, Micca PL, Fand I, Joel DD. Selective delivery of boron by the melanin precursor analog p-boronophenylalanine to tumors other than melanoma. Cancer Res 1990;50:138–41.

Mishima Y, Honda C, Ichibashi M, et al. Treatment of malignant melanoma by single neutron capture therapy with melanoma-seeking 10B-compound. Lancet 1989;1:388–9.

Mishima Y. Melanoma and nonmelanoma neutron capture therapy using gene therapy: overview. In: Larsson B, Crawford J, Weinreich, editors. Advances in neutron capture therapy. Vol. 1. Medicine and physics. Elsevier; 1997. p. 10–25.

Madoc-Jones H, Zamenhof R, Solares G, et al. A phase-I dose-escalation trial of boron neutron capture therapy for subjects with metastatic subcutaneous melanoma of the extremities. In: Mishima Y, editor. Cancer neutron capture therapy. New York and London: Plenum Press; 1996. p. 707–16.

Yoshino K, Suzuki A, Mori Y, et al. Improvement of solubility of p-boronophenylalanine by complex formation with monosaccharides. Strahlenther Onkol 1989;165:127–9.

Busse PM, Zamenhof RG, Harling OK, et al. The Harvard-MIT BNCT Program: overview of the clinical trials and translational research. Proceedings of the 11th International Congress of Radiation Research; 1999 Jul 18–23; Dublin, Ireland. Vol. 2. p. 702–9.

Gonzalez SJ, Bonomi MR, Santa Cruz GA, et al. First BNCT treatment of a skin melanoma in Argentina: dosimetric analysis and clinical outcome. Appl Radiat Isot 2004;61:1101–5.

Barth RF, Matalka KZ, Bailey MQ, et al. A nude rat model for neutron capture therapy of human intracerebral melanoma. Int J Radiat Oncol Biol Phys 1994;28:1079–88.

Barth RF, Yang W, Bartus RT, et al. Neutron capture therapy of intracerebral melanoma: enhanced survival and cure following blood-brain barrier opening to improve delivery of boronophenylalanine. Int J Radiat Oncol Biol Phys 2002;52:858–68.

Barth RF, Yang W, Rotaru JH, et al. Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine. Int J Radiat Oncol Biol Phys 2000;47:209–18.

Kato I, Ono K, Sakurai Y, et al. Effectiveness of BNCT for recurrent head and neck malignancies. Appl Radiat Isot 2004;61:1069–73.

Pinelli T, Zonta A, Altieri S, et al. TAOrMINA: from the first idea to the application to the human liver. In: M.W. Sauerwein, R. Moss and A. Wittig, editors. Research and Development in Neutron Capture Therapy, Bologna: Monduzzi Editore, International Proceedings Division; 2002. p. 1065–72.

Ringe B, Pichlmayr R, Wittekind C, Tusch G. Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg 1991;15:27085.

Iwatsuki S, Starzl TE, Sheahan DA, et al. Hepatic resection versus transplantation for hepatocellular carcinoma. Ann Surg 1991;214:221–8.

Pinelli T. Neutron capture therapy for liver cancer metastases. Abstracts of the 11th World Congress on Neutron Capture Therapy; 2004 Oct 11–15; Boston, MA. p. 52.

Suzuki M, Nagata K, Masunaga S, et al. Biodistribution of 10B in a rat liver tumor model following intra-arterial administration of sodium borocaptate (BSH)/degradable starch microspheres (DSM) emulsion. Appl Radiat Isot 2004;61:933–7.

Koivunoro H, Bleuel DL, Nastasi U, Lou TP, Reijonen J, Leung K-N. BNCT dose distribution in liver with epithermal D-D and D-T fusion-based neutron beams. Appl Radiat Isot 2004;61:853–9.

Chou FI, Chung HP, Chung RF, et al. Biological efficacy of BPA in malignant and normal liver cells. Abstract of the 11th World Congress on Neutron Capture Therapy; 2004 Oct 11–15; Boston, MA. p. 38.

Dahlström M, Capala J, Lindström P, Wasseson A, Lindström A. Accumulation of boron in human malignant glioma cells in vitro is cell type dependent. J Neurooncol 2004;68:199–205.

Goodman JH, Yang W, Barth RF, et al. Boron neutron capture therapy of brain tumors: biodistribution, pharmacokinetics, and radiation dosimetry of sodium borocaptate in glioma patients. Neurosurgery 2000;47:608–22.

Hideghéty K, Sauerwein W, Wittig A, et al. Tissue uptake of BSH in patients with glioblastoma in the EORTC 11961 phase I BNCT trial. J Neurooncol 2003;62:145–56.

Santa Cruz GA, Zamenhof RG. The microdosimetry of the 10B reaction in boron neutron capture therapy. A new generalized theory. Radiat Res 2004;162:702–10.

Imahori Y, Ueda S, Ohmori Y, et al. Flourine-18-labeled fluoroboronophenylalanine PET in patients with glioma. J Nucl Med 1998;39:325–33.

Imahori Y, Ueda S, Ohmori Y, et al. Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas: part 1. Clin Cancer Res 1998;4:1825–32.

Imahori Y, Ueda S, Ohmori Y, et al. Positron emission tomography-based boron neutron capture therapy using boronophenylalanine for high-grade gliomas: part 1. Clin Cancer Res 1998;4:1833–41.

Kabalka GW, Nichols TL, Smith GT, Miller LF, Khan MK, Busse PM. The use of positron emission tomography to develop boron neutron capture therapy treatment plans for metastatic malignant melanoma. J Neurooncol 2003;62:187–95.

Perry JR, DeAngelis LM, Schold SC, et al. Challenges in the design and conduct of phase III brain tumor therapy trials. Neurology 1997;49:912–17.

Shapiro W. Bias in uncontrolled brain tumor trials. Can J Neurol Sci 1997;24:269–70.

Stupp R, Dietrich P-Y, Kraljevic SO, et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 2002;20:1375–82.

Stupp R, Mason WP, Van Den Bent MJ, et al. Radiptherapy plus concomitant and adjuvant temozolimide for glioblastoma. N Engl J Med 2005;325:987–96.

Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncology 2004;22:2101–7.