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PubMed1993

Principles and history of neutron capture therapy.

Neutron capture therapy (NCT) is a form of radiation therapy using nuclides having a high propensity for capturing thermal neutrons and reacting with a prompt nuclear reaction (i.e. disintegration). If these nuclides are introduced selectively into tumor cells it is theoretically possible to destroy the tumor and to spare the surrounding normal tissue. The principles of this modality were described in 1936. First clinical trials in the USA from 1951 to 1961 using 10B resulted in failure. Since 1968 patients suffering from glioblastoma have been successfully treated in Japan by NCT with 10B and since 1987 another Japanese group has treated melanoma using NCT. The Japanese experiences and recent advances in the evaluation of tumor-affinitive boron-containing drugs have spurred interest in NCT. This article presents some basic physical notions and a historic overview of NCT that emphasizes the well documented early trials as well as some recent developments. Problems which occurred in the past now demand special efforts for a better understanding of the effects of NCT before starting new clinical trials in the next few years.

Boron Neutron Capture Therapy↗
PubMed1995

The influence of heavy water on boron requirements for neutron capture therapy.

Neutron penetration in tissue is a major limitation of thermal NCT, as such much work has centered upon the epithermal neutron beam in an effort to improve this situation. Further gains in neutron flux penetration, and thus therapeutic ratios, are possible if natural water is replaced with heavy water prior to therapy. Applying MCNP to a heterogeneous ellipsoidal skull/brain model, advantage depth and therapeutic depth parameters are studied as a function of heavy water replacement for a range of tumor to blood boron ratios. Both thermal (0.025 eV) and epithermal (2-7 keV) ideal neutron beams are analyzed. Using 10B ratios in the range of documented human uptake, the thermal advantage depth improved by approximately 0.7 cm for 20% D2O replacement, however, the therapeutic depth increased by less than half this value. For the epithermal beam, both the advantage depth and the therapeutic depth increased by over 1 cm. Effects of heavy water replacement on 10B requirements to therapeutically treat the midline of the brain are also evaluated.

Boron↗
PubMed1994

Cell survival measurements in an argon, aluminium and sulphur filtered neutron beam: a comparison with 24 keV neutrons and relevance to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) has been advanced as a suitable alternative therapy for the treatment of glioma. BNCT involves the selective uptake of a tumour with a boron-bearing substance and subsequent irradiation with a beam of neutrons. Previous attempts with BNCT have utilized thermal neutrons, but this involves resection of the scalp prior to treatment and is only possible with superficial tumours. An alternative is to use a beam of intermediate-energy neutrons which will produce a peak in the thermal neutron fluence at depth in tissue and so enable deep-seated tumours to be treated. A neutron beam with a mean energy of approximately 9 keV, obtained by filtering neutrons from a reactor with aluminium, argon and sulphur, has been used to explore the radiobiological advantage over thermal and 24 keV neutrons for BNCT. Irradiation of V79 and HeLa cells at various positions in a polythene phantom suggest that the beam is less cytotoxic for a given neutron fluence than the 24 keV neutron beam previously considered as an alternative to thermal neutrons for BNCT. However, optimization of boron distribution via the development of new compounds still appears to be necessary for BNCT to become a safe alternative option for the treatment of glioma.

Aluminum↗
PubMedDate not supplied

Boronated starburst dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy.

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy or thermal neutrons (< or = 0.025 eV) to yield high LET alpha particles and recoiling 7Li nuclei [10B + nth-->[11B]-->4He(alpha) + 7Li + 2.39 MeV]. Approximately 10(9) boron-10 atoms must be delivered to each target cell in order to sustain a lethal 10B(n,alpha)7Li reaction. If MoAbs are to be used for targeting boron-10, then it is essential that they recognize a surface membrane epitope that is highly expressed on tumor cells and that a large number of boron-10 atoms be attached to each antibody molecule. In order to heavily boronate MoAbs, we have utilized starburst dendrimers (SD), which are precise, spherical macromolecules composed of repetitive poly(amidoamino) groups. Second- and fourth-generation dendrimers, having 12 and 48 reactive terminal amino groups and molecular weights of 2414 and 10,632 Da, respectively, were boronated using an isocyanato polyhedral borane, Na(CH3)3NB10H8NCO. The boronated starburst dendrimers (BSD), in turn, were derivatized with m-maleimidobenzoyl N-hydroxysulfosuccinimide ester (sulfo-MBS). The MoAbIB16-6, which is directed against the murine B16 melanoma, was derivatized with N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). The MBS-derivatized BSD and SPDP-derivatized MoAb were reacted to yield stable immunoconjugates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Radiation dose heterogeneity in receptor and antigen mediated boron neutron capture therapy.

Boron neutron capture therapy, BNCT, might be a valuable tumour therapeutical modality for the treatment of cells that are difficult to handle with conventional methods such as surgery or external radiotherapy. The principle is that tumour associated 10B atoms capture thermal neutrons and thereby forms high-LET helium and lithium ions as reaction products. An interesting development is to conjugate 10B atoms to macromolecules that bind to tumour cells with over-expressed receptors or specific antigens. The targeting macromolecules might be receptor-ligands, antibodies or antibody-fragments containing 10B. The present study deals with the limitations of such an approach. One problem is the background dose from capture of neutrons in physiologically occurring elements, especially nitrogen. We showed, with computer simulations, that the background specific energy (the stochastic analogy of dose) in the cell nuclei, due to captures in nitrogen, had a wide spread and could be rather high, up to 3 Gy in some cells, when relevant neutron fluencies were applied. The maximal amount of 10B that can be delivered to single tumour cells due to receptor-ligand, receptor-antibody or antigen-antibody mediated binding is probably in the range 10(8)-10(10) atoms/cell. Our calculations showed that the tumour cells had to contain about 10(9) 10B/cell to give a therapeutically interesting dose to the nuclei of the targeted cells. The doses were highest when the boron was in the cell nucleus. There was also a wide spread of specific energy absorbed by the nuclei after neutron capture in 10B. When, for example, 10(8) 10(10)B/nucleus were applied the specific energy to the analysed nuclei varied from 0 Gy up to about 7 Gy. These variations were due to the stochastic nature of the capture processes. Some helium or lithium ion tracks passed through the centre of the cell nuclei delivering a lot of energy, some passed through only a smaller part delivering small amounts of energy and sometimes the nuclei escaped without any hits at all. The results were obtained when relevant neutron fluencies (2-5 x 10(12) n/cm2) were applied. Increased neutron fluencies gave higher doses both due to capture in boron and in nitrogen but in order to improve the ratio between the dose to targeted tumour cells and the dose to normal cells, the number of 10B atoms in the targeted cells had to be increased and/or the boron placed in the cell nuclei.

Boron↗
PubMed1992

Present status of boron neutron capture therapy.

The neutron capture reaction 10B(1n,4He)7Li produces two energetic particles, 4He2+ and 7Li3+ that are strongly cell toxic. Due to the short range of these nuclear fragments (5-9 microns) mainly those cells that have bound or internalized a 10B-containing substance are growth-inactivated. The most critical and difficult step in an efficient boron neutron capture therapy (BNCT) is the tumour targeting. It is today possible to synthesize a large number of boron compounds and conjugate them to tumour-seeking macromolecules, such as monoclonal antibodies or different polypeptides. The boron-containing substances presently considered for therapy are sulfhydryl boron hydride (BSH) and boron-phenylalanine, (BPA) for the treatment of gliomas and malignant melanomas respectively. Other boronated compounds considered are ligands for receptor-amplified tumour cells, antibodies for tumour cells with specific antigens and thioureas for treatment of melanotic melanomas. The required boron concentration is given by the relative dose due to neutron capture in 10B and that of the competing capture reactions in nitrogen and hydrogen. Capture in nitrogen produces protons with a range of about 10-11 microns and this gives a radiation dose to all cells in the neutron activated area. Calculations show that the local concentration of 10B near the critical radiation target, DNA, must be higher than 10 ppm (10 micrograms/g). Increased emphasis will be put on the development of combinations of treatments that fulfil the requirements for attacking the microscopic spread of the tumour.

Boron↗
PubMed1994

Present status and perspectives of boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a mode of radiotherapy with great attractiveness, but also with a burden of past failure. In this review, the principles of BNCT, the reasons for its past failure, its present clinical application, and the on-going developmental work towards clinical trials are described.

Animals↗
PubMed1996

Ion microscopy imaging of 10B from p-boronophenylalanine in a brain tumor model for boron neutron capture therapy.

Boron neutron capture therapy (BNCT), a binary treatment modality that can potentially irradiate tumor tissue within cellular dimensions, is critically dependent on the preferential delivery of 10B to individual neoplastic cells. In this study, ion microscopy was used to quantitatively evaluate the selectivity of p-boronophenylalanine-fructose (BPA-F) in the rat 9L gliosarcoma brain tumor model. With a spatial resolution of approximately 0.5 microm, ion microscopy images show that BPA-F delivers 3.5 times more boron to the main tumor mass [99 +/- 36 microg/g tissue (mean +/- SD)] than to the contiguous normal brain (27 +/- 12 microg/g tissue). A similar, but lower, accumulation was observed away from the main tumor mass in small clusters of neoplastic cells (47 +/- 15 microg/g tissue) invading the surrounding brain (16 +/- 8 microg/g tissue). These findings establish for the first time the selectivity of BPA-F to the neoplastic cells invading the normal brain and provide a much-needed baseline measurement of the distribution of a clinically approved BNCT drug. Given the propensity for malignant brain tumors to infiltrate the surrounding normal brain, these observations have particular significance for clinical trials of BNCT for human glioblastoma multiforme using the drug BPA-F.

Animals↗
PubMed1993

Intracellular distribution of various boron compounds for use in boron neutron capture therapy.

The neutron capture reaction in boron (10B(n, alpha)7Li) generates two short-range particles with high linear energy transfer. The effect of neutron capture therapy depends on the selective localization of 10B atoms in target cells. The determination of the distribution of boron compounds in cancer cells at the subcellular level is required for the understanding of the effect of this treatment. The monomeric sulfhydryl borane (BSH) compound has been used clinically in Japan and preclinically in the U.S.A. Recently, new compounds have been developed: a dimeric sulfhydryl borane (BSSB), a boronophenylalanine (BPA), and two porphyrin complexes (BOPP and VCDP). This study demonstrates that the porphyrin complexes (BOPP and VCDP) are more cytotoxic than the other three compounds to the rat 9L gliosarcoma cell line. Using atomic absorption spectrophotometry to determine boron content for cellular uptake studies of these agents, we found that of the five compounds tested BOPP (25 microM) exposure resulted in the greatest boron uptake averaging 305 ng B/10(6) cells. BSSB (500 microM) was second averaging 93 ng B/10(6) cells, BSH (500 microM) third averaging 62 ng B/10(6) cells, VCDP (25 microM) fourth averaging 58 ng B/10(6) cells, and BPA (500 microM) fifth averaging 7.4 ng B/10(6) cells. Data on the distribution of boron in the nuclei, mitochondria, lysosomes, microsomes, and cytosomes of 9L cells are also presented.

Animals↗
PubMed1997

Study of boron neutron capture therapy used neutron source with protons bombarding a thick 9Be target.

Neutron sources created by 4-, 3.5-, and 3-MeV protons striking a thick beryllium target were studied via the time-of-flight technique. Protons were accelerated by the Peking University 4.5 MV electrostatic accelerator. Two disk-shaped 9Be targets with thickness 1.5 and 3 mm were used in the measurements. The time-of-flight spectra were observed at zero degrees with respect to the incident proton beam. The analysis to these time-of-flight spectra is given. The time-of-flight spectra were converted to the energy spectra and compared to a neutron spectrum of 7Li(p, n)7 Be reaction with incident energy 2.5 MeV, which was also measured in this work. Restricted by the spectrometer itself, the threshold of the measurements is 400 keV. The results show that by using several MeV protons bombarding a thick beryllium target, reactions other than 9Be(p, n)9B produce significant contributions to the neutron yield with energy less than 1 MeV.

Beryllium↗
PubMed1996

Targeted drug delivery for boron neutron capture therapy.

PURPOSE: Boron neutron capture therapy (BNCT) is a form of radiochemotherapy that is becoming increasingly important for the treatment of malignant gliomas, malignant melanomas and other forms of cancer. Targeted delivery of boron to tumors is a critical prerequisite for successful BNCT. METHODS: Strategies that involve synthetic chemical approaches and biochemical and biophysical approaches are employed to meet this requirement. Compounds developed for targeting to tumors include borocaptate sodium (BSH) and p-boronophenylalanine (BPA) which are currently in clinical use. RESULTS: Boronated porphyrins, nucleosides, nucleotides and other boronated compounds show potentials as targeting molecules. Conjugation of boron compounds to macromolecules such as monoclonal antibodies, epidermal growth factor and dextran is also employed for active or passive tumor targeting. CONCLUSIONS: Boron delivery via microparticulate carriers such as liposomes, high density lipoproteins and microcapsules is also attractive for its potential application in BNCT.

Animals↗
PubMed1995

A novel approach to the microdosimetry of neutron capture therapy. Part I. High-resolution quantitative autoradiography applied to microdosimetry in neutron capture therapy.

A novel approach to the microdosimetry of neutron capture therapy has been developed using high-resolution quantitative autoradiography (HRQAR) and two-dimensional Monte Carlo simulation. This approach has been applied using actual cell morphology (nuclear and cytoplasmic cell structures) and the measured microdistribution of boron-10 in a transplanted murine brain tumor (GL261) containing p-boronophenylalanine (BPA) as the boron compound. The 2D Monte Carlo transport code for the alpha and 7Li charged particles from the 10B(n,alpha)7Li reactions has been developed as a surrogate to a full 3D approach to calculate a variety of different microdosimetric parameters. The HRQAR method and the surrogate 2D Monte Carlo approach are described in detail and examples of their use are presented.

Animals↗
PubMed1987

Preliminary study for application of anti-alpha-fetoprotein monoclonal antibody to boron-neutron capture therapy.

Boron-neutron capture therapy (BNCT) has been applied clinically, especially in brain-neuro surgery. We intended to expand the application of BNCT for the treatment of abdominal cancers and tried to determine whether MoAb (monoclonal antibody) against AFP (alpha-fetoprotein) could be useful tool to deliver boron-10 (10B) to AH-66 hepatoma cells for BNCT. Firstly, MoAb was boronated by mixing with 10B-compound (Cs2 10B12H11SH) by using N-succinimidyl 3(2-pyridyldithio)propionate (SPDP). Numbers of 10B atoms bound to an antibody molecule were in proportion to the dose of 10B-compound added, and maximum number of 10B atoms conjugated to an antibody molecule was approximately 1240. Secondly, using this boronated MoAb, 10B was delivered to AH-66 cells, and 11 X 10(9) 10B atoms were estimated to be on and/or in an AH-66 cell. After the irradiation with thermal neutron, boronated AH-66 cells showed decreasing uptake of [3H]TdR in proportion to the number of 10B atoms bound to and/or incorporated into the tumor cells. These results indicate that 10B atoms delivered by MoAb exert cytotoxic effect on AH-66 cells in a dose dependent manner by thermal neutron irradiation.

Animals↗
PubMed1993

RBE in fast neutron therapy and in boron neutron capture therapy. A useful concept or a misuse?

In high-LET radiation therapy, radiation quality and radiation quality differences have to be taken into account and specified. In fast neutron therapy, an operational approach has been adopted which is based on the concept of "clinical RBE". The paper discusses the quantities of RBE (relative biological effectiveness), reference RBE and clinical RBE and their relationship and significance in radiation therapy. In particular, the difference between the well defined RBE in radiation biology and the clinical RBE which is based on the judgement of radiotherapists is elucidated and emphasized. The clinical RBE is based on the reference RBE and implicitly includes differences in physical selectivity of the irradiation beams and clinical experience. The particular aspects of radiation quality in boron neutron capture therapy (BNCT) are due to the poor penetration of the primary beam, the inhomogeneity of the spatial distribution of 10B nuclides in the irradiated tissue and the short range of the alpha-particles emitted after neutron capture in 10B. The related problems in accounting for radiation quality in BNCT and in the applicability of the clinical RBE concept are discussed.

Boron Neutron Capture Therapy↗
PubMed1994

[Neutron capture therapy for cancer].

Boron neutron capture therapy (BNCT) is a selective radiotherapy using boron-10 which absorbs thermal neutrons and releases high LET alpha particles by 10B(n, alpha)7Li reaction. In this paper, the present status of BNCT for malignant melanoma was introduced. As a melanoma-targetting 10B-compound, 10B-paraboronophylalanine (BPA) was used. It was administered by multiple subcutaneous injection or intravenous drip infusion. We adopted the maximum tolerance dose to the skin as a therapeutic dose regardless of the tumor 10B concentration, because we cannot directly measure it. For this purpose, an approximation of skin concentration was made using blood data just after the administration. We treated 14 melanoma patients in this way and obtained good local control of the tumor with tolerable skin reaction. More experience with logical analysis and basic research is necessary for further development of this therapy.

Boron Compounds↗
PubMed1994

Concomitant boron-neutron capture therapy during fast-neutron irradiation of a rat glioma.

PURPOSE: Fast-neutron irradiation and boron-neutron capture therapy (BNCT) have been independently investigated as treatments for malignant disease. This study tested the feasibility of enhancing fast-neutron irradiation with concomitant BNCT. MATERIALS AND METHODS: Seventeen male Fisher rats, each weighing 180-200 g and bearing 36B10 gliomas, were irradiated with graded doses of fast-neutron radiation. Half of the animals received an L-para-boronophenylalanine (BPA) fructose complex prior to treatment. An in vitro colony-forming assay was used to measure surviving fraction. RESULTS: A significantly lower surviving fraction was noted in the tumors from the BPA group compared with those receiving neutrons alone at the three lower neutron doses (P < .005). With use of a linear quadratic curve fit of cell survival, the dose modifying factor was 1.32 at the 0.10 surviving fraction. Mean tumor boron concentration was 68.4 micrograms/g. CONCLUSIONS: BNCT enhancement of fast-neutron irradiation is feasible in an in vivo tumor system.

Animals↗