Compound Biological Effectiveness Research Articles

Assessing the biological effects of boron neutron capture therapy through cellular DNA damage repair model.

Boron neutron capture therapy (BNCT) is a targeted radiotherapy that relies on the 10B (n, α) 7Li reaction, which produces secondary particles with high linear energy transfer (LET), leading to a high relative biological effectiveness (RBE) in tumors. The biological effectiveness of BNCT is influenced by factors such as boron distribution and concentration, necessitating improved methods for assessing its radiobiological effects and clarifying the sensitivity of the differences in different factors to the biological effects. This paper introduces a method to evaluate the biological effects of BNCT using the cellular repair model. This method aims to overcome some of the limitations of current evaluation approaches. The primary goal is to provide guidance for clinical treatments and the development of boron drugs, as well as to investigate the impact of the synergistic effects of mixed radiation fields in BNCT on treatment outcomes. The approach involves three key steps: first, extending the radial energy deposition distribution of BNCT secondary particles using Geant4-DNA. This allows for the calculation of initial DNA double-strand breaks (DSBs) distributions for a given absorbed dose. Next, the obtained initial DSB distributions are used for DNA damage repair simulations to generate cell survival curves, then thereby quantifying RBE and compound biological effectiveness (CBE). The study also explores the synergistic effects of the mixed radiation fields in BNCT on assessing biological effects were also explored in depth. The results showed that the RBE of boronophenylalanine (BPA) and sodium borocaptate (BSH) drugs at cell survival fraction 0.01 was 2.50 and 2.15, respectively. The CBE of the boron dose component was 3.60 and 0.73, respectively, and the RBE of the proton component was 3.21, demonstrating that BPA has a significantly higher biological impact than BSH due to superior cellular permeability. The proton dose significance in BNCT treatment is also underscored, necessitating consideration in both experimental and clinical contexts. The study demonstrates that synergistic effects between disparate radiation fields lead to increased misrepairs and enhanced biological impact. Additionally, the biological effect diminishes with rising boron concentration, emphasizing the need to account for intercellular DNA damage heterogeneity. This methodology offers valuable insights for the development of new boron compounds and precise assessment of bio-weighted doses in clinical settings and can be adapted to other therapeutic modalities.

Incorporating boron distribution variations in microdosimetric kinetic model-based relative biological effectiveness calculations for boron neutron capture therapy.

This study introduces the MKM_B model, an approach derived from the MKM model, designed to evaluate the biological effectiveness of Boron Neutron Capture Therapy (BNCT) in the face of challenges from varying microscopic boron distributions. The model introduces a boron compensation factor, allowing for the assessment of compound Biological Effectiveness (CBE) values for different boron distributions. Utilizing the TOPAS simulation platform, the lineal energy spectrum of particles in BNCT was simulated, and the sensitivity of the MKM_B model to parameter variations and the influence of cell size on the model were thoroughly investigated. The CBE values for 10B-boronphenylalanine (BPA) and 10B-sodium (BSH) were determined to be 3.70 and 1.75, respectively. These calculations were based on using the nucleus radius of 2.5 μm and the cell radius of 5 μm while considering a 50% surviving fraction. It was observed that as cell size decreased, the CBE values for both BPA and BSH increased. Additionally, the model parameter rd was identified as having the most significant impact on CBE, with other parameters showing moderate effects. The development of the MKM_B model enables the accurate prediction of CBE under different boron distributions in BNCT. This model offers a promising approach to optimize treatment planning by providing increased accuracy in biological effectiveness.

Primary study of the relative and compound biological effectiveness model for boron neutron capture therapy based on nanodosimetry.

The current radiobiological model employed for boron neutron capture therapy (BNCT) treatment planning, which relies on microdosimetry, fails to provide an accurate representation the biological effects of BNCT. The precision in calculating the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) plays a pivotal role in determining the therapeutic efficacy of BNCT. Therefore, this study focuses on how to improve the accuracy of the biological effects of BNCT. The purpose of this study is to propose new radiation biology models based on nanodosimetry to accurately assess RBE and CBE for BNCT. Nanodosimetry, rooted in ionization cluster size distributions (ICSD), introduces a novel approach to characterize radiation quality by effectively delineating RBE through the ion track structure at the nanoscale. In the context of prior research, this study presents a computational model for the nanoscale assessment of RBE and CBE. We establish a simplified model of DNA chromatin fiber using the Monte Carlo code TOPAS-nBio to evaluate the applicability of ICSD to BNCT and compute nanodosimetric parameters. Our investigation reveals that both homogeneous and heterogeneous nanodosimetric parameters, as well as the corresponding biological model coefficients α and β, along with RBE values, exhibit variations in response to varying intracellular 10B concentrations. Notably, the nanodosimetric parameter effectively captures the fluctuations in model coefficients α and RBE. Our model facilitates a nanoscale analysis of BNCT, enabling predictions of nanodosimetric quantities for secondary ions as well as RBE, CBE, and other essential biological metrics related to the distribution of boron. This contribution significantly enhances the precision of RBE calculations and holds substantial promise for future applications in treatment planning.

Calculation of the DNA damage yield and relative biological effectiveness in boron neutron capture therapy via the Monte Carlo track structure simulation.

Objective.Boron neutron capture therapy (BNCT) is an advanced cellular-level hadron therapy that has exhibited remarkable therapeutic efficacy in the treatment of locally invasive malignancies. Despite its clinical success, the intricate nature of relative biological effectiveness (RBE) and mechanisms responsible for DNA damage remains elusive. This work aims to quantify the RBE of compound particles (i.e. alpha and lithium) in BNCT based on the calculation of DNA damage yields via the Monte Carlo track structure (MCTS) simulation.Approach. The TOPAS-nBio toolkit was employed to conduct MCTS simulations. The calculations encompassed four steps: determination of the angle and energy spectra on the nuclear membrane, quantification of the database containing DNA damage yields for ions with specific angle and energy, accumulation of the database and spectra to obtain the DNA damage yields of compound particles, and calculation of the RBE by comparison yields of double-strand break (DSB) with the reference gamma-ray. Furthermore, the impact of cell size and microscopic boron distribution was thoroughly discussed.Main results. The DSB yields induced by compound particles in three types of spherical cells (radius equal to 10, 8, and 6μm) were found to be 13.28, 17.34, 22.15 Gy Gbp-1for boronophenylalanine (BPA), and 1.07, 3.45, 8.32 Gy Gbp-1for sodium borocaptate (BSH). The corresponding DSB-based RBE values were determined to be 1.90, 2.48, 3.16 for BPA and 0.15, 0.49, 1.19 for BSH. The calculated DSB-based RBE showed agreement with experimentally values of compound biological effectiveness for melanoma and gliosarcoma. Besides, the DNA damage yield and DSB-based RBE value exhibited an increasing trend as the cell radius decreased. The impact of the boron concentration ratio on RBE diminished once the drug enrichment surpasses a certain threshold.Significance. This work is potential to provide valuable guidance for accurate biological-weighted dose evaluation in BNCT.

The effects of BPA-BNCT on normal bone: determination of the CBE value in mice‡.

Boron neutron capture therapy (BNCT) with p-boronophenylalanine (BPA) is expected to have less effect on the decrease in normal bone strength than X-ray therapy. However, the compound biological effectiveness (CBE) value necessary to convert the boron neutron capture reaction (BNCR) dose into a bioequivalent X-ray dose has not been determined yet. The purpose of this study was to evaluate the influence of BNCT on normal bone in mice and to elucidate the CBE factor. We first searched the distribution of BPA in the normal bone of C3H/He mice and then measured the changes in bone strength after irradiation. The CBE value was determined when the decrease in bone strength was set as an index of the BNCT effect. The 10B concentrations in the tibia after subcutaneous injection of 125, 250 and 500mg/kg BPA were measured by prompt gamma-ray spectroscopy and inductively coupled plasma (ICP)-atomic emission spectrometry. The 10B mapping in the tibia was examined by alpha-track autoradiography and laser ablation-ICP-mass spectrometry. The 10B concentration increased dose-dependently; moreover, the concentrations were maintained until 120min after BPA administration. The administered 10B in the tibia was abundantly accumulated in the growth cartilage, trabecular bone and bone marrow. The bone strength was analyzed by a three-point bending test 12weeks after irradiation. The bending strength of the tibia decreased dose-dependently after the irradiation of X-ray, neutron and BNCR. The CBE factor was obtained as 2.27 by comparing these dose-effect curves; the value determined in this study will enable an accurate dosimetry of normal bone.

The impact of TP53 status of tumor cells including the type and the concentration of administered 10B delivery agents on compound biological effectiveness in boron neutron capture therapy.

Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or neo vector (SAS/neo) were inoculated subcutaneously into left hind legs of nude mice. After the subcutaneous administration of a 10B-carrier, boronophenylalanine-10B (BPA) or sodium mercaptododecaborate-10B (BSH), at two separate concentrations, the 10B concentrations in tumors were measured using γ-ray spectrometry. The tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) tumor cells, then were administered with BPA or BSH. Subsequently, the tumors were irradiated with reactor neutron beams during the time of which 10B concentrations were kept at levels similar to each other. Following irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU. In both SAS/neo and SAS/mp53 tumors, the compound biological effectiveness (CBE) values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. The higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in SAS/neo tumors and the use of BPA than in SAS/mp53 tumors and BSH, respectively. The values for BPA that delivers into solid tumors more dependently on uptake capacity of tumor cells than BSH became more alterable. Tumor micro-environmental heterogeneity might partially influence on the CBE value. The CBE value can be regarded as one of the indices showing the level of intratumor heterogeneity.

Multi-Targeted Neutron Capture Therapy Combined with an 18 kDa Translocator Protein-Targeted Boron Compound Is an Effective Strategy in a Rat Brain Tumor Model

Boron neutron capture therapy (BNCT) has been adapted to high-grade gliomas (HG); however, some gliomas are refractory to BNCT using boronophenylalanine (BPA). In this study, the feasibility of BNCT targeting the 18 kDa translocator protein (TSPO) expressed in glioblastoma and surrounding environmental cells was investigated. Three rat glioma cell lines, an F98 rat glioma bearing brain tumor model, DPA-BSTPG which is a boron-10 compound targeting TSPO, BPA, and sodium borocaptate (BSH) were used. TSPO expression was evaluated in the F98 rat glioma model. Boron uptake was assessed in three rat glioma cell lines and in the F98 rat glioma model. In vitro and in vivo neutron irradiation experiments were performed. DPA-BSTPG was efficiently taken up in vitro. The brain tumor has 16-fold higher TSPO expressions than its brain tissue. The compound biological effectiveness value of DPA-BSTPG was 8.43 to F98 rat glioma cells. The boron concentration in the tumor using DPA-BSTPG convection-enhanced delivery (CED) administration was approximately twice as high as using BPA intravenous administration. BNCT using DPA-BSTPG has significant efficacy over the untreated group. BNCT using a combination of BPA and DPA-BSTPG gained significantly longer survival times than using BPA alone. DPA-BSTPG in combination with BPA may provide the multi-targeted neutron capture therapy against HG.

ET-4 BASIC RESEARCH OF BORON NEUTRON CAPTURE THERAPY USING A NOVEL BORON COMPOUND TARGETED TO INTEGRIN

Abstract Background Boron neutron capture therapy (BNCT) is a particle radiation modality capable of selectively destroying tumor cells. The most commonly used boron compound for BNCT is boronphenylalanine (BPA). BPA is taken up into the tumor cell via the L-type aminoacid transporter (LAT-1). However, there are some BPA-refractory situations. Therefore, a novel boron compound is expected to improve the therapeutic performance of BNCT. We focused on integrinαvβ3, which is overexpressed in malignant gliomas as in many cancer cells, and have developed cRGD-MID-AC, a conjugate of cyclic RGD (cRGD), which selectively inhibited integrinαvβ3, and MID-AC, which we have already reported as effective on BNCT as BPA as a boron compound in F98 rat glioma models. We evaluated the efficacy of BNCT using this novel compound.Methods: F98 glioma cells were exposed to BPA, cRGD-MID-AC, and cRGD-MID for cellular uptake and neutron irradiation experiment. Intracellular boron concentrations and compound biological effectiveness (CBE) for each boron compound was calculated. After intravenous administration (i.v.) of cRGD-MID-AC or BPA, the biodistribution of boron compounds was measured and neutron irradiation experiment were performed in F98 rat glioma models. Results Intracellular boron concentrations of BPA and cRGD-MID-AC were increased gradually at all exposed time, and CBE for cRGD-MID-AC was comparable to that for BPA. In cRGD-MID-AC, the boron concentration in the tumor was the highest at 8 h after i.v. and tended to be retained longer at 24h. In vivo neutron irradiation experiment, long-term survival was observed only in the group irradiated 8 h after cRGD-MID-AC i.v.. These experiments suggest that cRGD-MID-AC has sufficient cell-killing effect and may be more effective in vivo. Conclusion cRGD-MID-AC has a tumor accumulation mechanism different from that of BPA, and could be an effective boron carrier in BNCT for malignant gliomas.

Boron Neutron Capture Therapy (BNCT) for Cutaneous Malignant Melanoma Using 10B-p-Boronophenylalanine (BPA) with Special Reference to the Radiobiological Basis and Clinical Results.

BNCT is a radiotherapeutic method for cancer treatment that uses tumor-targeting 10B-compounds. BNCT for cutaneous melanoma using BPA, a phenylalanine derivative, was first initiated by Mishima et al. in 1987. This article reviews the radiobiological basis of melanoma control and damage to normal tissues as well as the results of clinical studies. Experimental studies showed that the compound biological effectiveness (CBE) values of the 10B (n, α)7Li reaction for melanoma control ranged from 2.5 to 3.3. The CBE values of the 10B (n, α)7Li reaction for skin damage ranged from 2.4 to 3.7 with moist desquamation as the endpoint. The required single radiation dose for controlling human melanoma was estimated to be 25 Gy-Eq or more by analyzing the 50% tumor control dose data of conventional fractionated radiotherapy. From the literature, the maximum permissible dose to human skin by single irradiation was estimated to be 18 Gy-Eq. With respect to the pharmacokinetics of BPA in patients with melanoma treated with 85–350 mg/kg BPA, the melanoma-to-blood ratio ranged from 2.1–3.8 and the skin-to-blood ratio was 1.31 ± 0.22. Good local tumor control and long-term survival of the patients were achieved in two clinical trials of BNCT conducted in Japan.

Response of Normal Tissues to Boron Neutron Capture Therapy (BNCT) with 10B-Borocaptate Sodium (BSH) and 10B-Paraboronophenylalanine (BPA).

Boron neutron capture therapy (BNCT) is a cancer-selective radiotherapy that utilizes the cancer targeting 10B-compound. Cancer cells that take up the compound are substantially damaged by the high liner energy transfer (LET) particles emitted mainly from the 10B(n, α7Li reaction. BNCT can minimize the dose to normal tissues, but it must be performed within the tolerable range of normal tissues. Therefore, it is important to evaluate the response of normal tissues to BNCT. Since BNCT yields a mixture of high and low LET radiations that make it difficult to understand the radiobiological basis of BNCT, it is important to evaluate the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) factors for assessing the responses of normal tissues to BNCT. BSH and BPA are the only 10B-compounds that can be used for clinical BNCT. Their biological behavior and cancer targeting mechanisms are different; therefore, they affect the CBE values differently. In this review, we present the RBE and CBE values of BPA or BSH for normal tissue damage by BNCT irradiation. The skin, brain (spinal cord), mucosa, lung, and liver are included as normal tissues. The CBE values of BPA and BSH for tumor control are also discussed.

Mechanistic Modeling of the Relative Biological Effectiveness of Boron Neutron Capture Therapy.

Accurate dosimetry and determination of the biological effectiveness of boron neutron capture therapy (BNCT) is challenging because of the mix of different types and energies of radiation at the cellular and subcellular levels. In this paper, we present a computational, multiscale system of models to better assess the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) of several neutron sources as applied to BNCT using boronophenylalanine (BPA) and a potential monoclonal antibody (mAb) that targets HER-2-positive cells with Trastuzumab. The multiscale model is tested against published in vitro and in vivo measurements of cell survival with and without boron. The combined dosimetric and radiobiological model includes an analytical formulation that accounts for the type of neutron source, the tissue- or cancer-specific dose–response characteristics, and the microdistribution of boron. Tests of the model against results from published experiments with and without boron show good agreement between modeled and experimentally determined cell survival for neutrons alone and in combination with boron. The system of models developed in this work is potentially useful as an aid for the optimization and individualization of BNCT for HER-2-positive cancers, as well as other cancers, that can be targeted with mAb or a conventional BPA compound.

Implications of radiation microdosimetry for accelerator-based boron neutron capture therapy: a radiobiological perspective.

Boron neutron capture therapy (BNCT) has great potential to selectively destroy cancer cells while sparing surrounding normal cells. The basic concept of BNCT was developed in the 1930s, but it has not yet been commonly used in clinical practice, even though there is now a large number of experimental and translational studies demonstrating its marked therapeutic potential. With the development of neutron accelerators that can be installed in medical institutions, accelerator-based BNCT is expected to become available at several medical institutes around the world in the near future. In this commentary, from the point of view of radiation microdosimetry, we discuss the biological effects of BNCT, especially the underlying mechanisms of compound biological effectiveness. Radiobiological perspectives provide insight into the effectiveness of BNCT in creating a synergy effect in the field of clinical oncology.

Reevaluation of CBE value of BPA for hepatocytes

The compound biological effectiveness (CBE) value of boronophenylalanine (BPA) for hepatocytes was experimentally determined for the purpose of boron neutron capture therapy (BNCT) for liver tumors. In this study, the critical reevaluation of previous value was performed. In previous experimental studies, the contribution of β component of dose was ignored in the response curve to X-ray. X-ray dose cell survival curves were estimated by combining the α/β values obtained in the ordinary micronucleus (MN) assay with the curve of MN-negative cell fraction (MN(−)F) to dose. This curve was compared to the boron neutron capture reaction (BNCR) dose curve. As a result, the CBE value was 4 at doses close to 0 Gy, decreasing to about 1.0 at doses close to 4.5 Gy. The new value is smaller than the previous value 4.2. This indicates that the bioequivalent dose to normal liver is lower than previously expected. Therefore, higher doses can be given to the tumor.

Effect of a change in reactor power on response of murine solid tumors in vivo, referring to impact on quiescent tumor cell population

Purpose: To examine the effect of a change in reactor power on the response of solid tumors, referring to impact on quiescent (Q) tumor cell population.Materials and methods: Tumor-bearing mice received 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) tumor cells, and were treated with boronophenylalanine-10B (BPA) or sodium mercaptododecaborate-10B (BSH). After reactor neutron beam irradiation at a power of 1 or 5 MW with an identical beam spectrum, cells from tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled Q and total (P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU.Results: After neutron irradiation with or without 10B-carrier, radio-sensitivity was reduced by decreasing reactor power in both cells, especially in Q cells and after irradiation with BPA. The values of relative and compound biological effectiveness were larger at a power of 5 MW and in Q cells than at a power of 1 MW and in total cells, respectively. The sensitivity difference between total and Q cells was widened when combined with 10B-carrier, especially with BPA, and through decreasing reactor power.Conclusion: 5 MW is more advantageous than 1 MW for boron neutron capture therapy.

An analysis of the structure of the compound biological effectiveness factor

This report is an analysis of the structure of the compound biological effectiveness (CBE) factor. The value of the CBE factor previously reported was revalued for the central nervous system, skin and lung. To describe the structure, the following terms are introduced: the vascular CBE (v-CBE), intraluminal CBE (il-CBE), extraluminal CBE (el-CBE) and non-vascular CBE (nv-CBE) factors and the geometric biological factor (GBF), i.e. the contributions that are derived from the total dose to the vasculature, each dose to vasculature from the intraluminal side and the extraluminal side, the dose to the non-vascular tissue and the factor to calculate el-CBE from il-CBE, respectively. The el-CBE factor element was also introduced to relate il-CBE to el-CBE factors. A CBE factor of 0.36 for disodium mercaptoundecahydrododecaborate (BSH) for the CNS was independent of the 10B level in the blood; however, that for p-Boron-L-phenylalanine (BPA) increased with the 10B level ratio of the normal tissue to the blood (N/B). The CBE factor was expressed as follows: factor = 0.32 + N/B × 1.65. The factor of 0.32 at 0 of N/B was close to the CBE factor for BSH. GBFs had similar values, between BSH and BPA, 1.39 and 1.52, respectively. The structure of the CBE factor for BPA to the lung was also elucidated based on this idea. The factor is described as follows: CBE factor = 0.32 + N/B × 1.80. By this elucidation of the structure of the CBE factor, it is expected that basic and clinical research into boron neutron capture therapy will progress.

Determination of the Compound Biological Effectiveness (CBE) Factors Based on the <i>ISHIYAMA-IMAHORI</i> Deterministic Parsing Model with the Dynamic PET Technique

Purpose: In defining the biological effects of the 10B(n, α)7Li neutron capture reaction, we have proposed a deterministic parsing model (ISHIYAMA-IMAHORI model) to determine the Compound Biological Effectiveness (CBE) factor in Borono-Phenyl-Alanine (BPA)-mediated Boron Neutron Capture Therapy (BNCT). In present paper, we demonstrate a specific method of how the application of the case of application to actual patient data, which is founded on this model for tissues and tumor. Method: To determine the CBE factor, we derived the following new calculation formula founded on the deterministic parsing model with three constants, CBE0, F, n and the eigen value Nth/Nmax. (1), where, Nth and Nmax are the threshold value of boron concentration of N and saturation boron density and CBE0, F and n are given as 0.5, 8 and 3, respectively. In order to determine Nth and Nmax in the formula, sigmoid logistic function was employed for 10B concentration data, Db(t) obtained by dynamic PET technique. (2), where, A, a and t0 are constants. Results and Conclusion: From the application of sigmoid function to dynamic PET data, it is concluded that the Nth and Nmax for tissue and tumor are identified with the parameter constants in the sigmoid function in Equation (2) as: (3). And the calculated CBE factor values obtained from Equation (1), with Nth/Nmax.

Assessment of biological effectiveness of boron neutron capture therapy in primary and metastatic melanoma cell lines

Purpose: In order to optimize the effectiveness of Boron Neutron Capture Therapy (BNCT), Relative Biological Effectiveness (RBE) and Compound Biological Effectiveness (CBE) were determined in two human melanoma cell lines, M8 and Mel-J cells, using the amino acid p-boronophenylalanine (BPA) as boron carrier.Materials and methods: The effects of BNCT on the primary amelanotic cell line M8 and on the metastatic pigmented melanoma cell line Mel-J were studied using colony formation assay. The RBE values were determined using both a gamma ray source, and the neutron beam from the Nuclear Reactor of the National Atomic Energy Commission (RA-3). For the determination of the RBE, cells were irradiated with increasing doses of both sources, between 1 and 8 Gy; and for the determination of CBE factors, the cells were pre-incubated with BPA before irradiation. Afterwards, the cell surviving fraction (SF) was determined for each treatment.Results: Marked differences were observed between both cell lines. Mel-J cells were more radioresistant than the M8 cell line. The clonogenic assays showed that for a SF of 1%, the RBE values were 1.3 for M8 cells and 1.5 for Mel-J cells. Similarly, the CBE values for a 1% SF were 2.1 for M8 and 3 for Mel-J cell lines. For the endpoint of 0.1% of SF the RBE values obtained were 1.2 for M8 and 1.4 for Mel-J cells. Finally, CBE values calculated for a 0.1% were 2 and 2.6 for M8 and Mel-J cell lines respectively. In order to estimate the uptake of the non-radioactive isotope Boron 10 (10B), a neutron induced autoradiographic technique was performed showing discrepancies in 10B uptake between both cell lines.Conclusions: These obtained in vitro results are the first effectiveness factors determined for human melanoma at the RA-3 nuclear reactor and show that BNCT dosimetry planning for patients could be successfully performed using these new factors.

The dependency of compound biological effectiveness factors on the type and the concentration of administered neutron capture agents in boron neutron capture therapy.

PurposeTo examine the effect of the type and the concentration of neutron capture agents on the values of compound biological effectiveness (CBE) in boron neutron capture therapy.Methods and materialsAfter the subcutaneous administration of a 10B-carrier, boronophenylalanine-10B (BPA) or sodium mercaptododecaborate-10B (BSH), at 3 separate concentrations, the 10B concentrations in tumors were measured by γ-ray spectrometry. SCC VII tumor-bearing C3H/He mice received 5-bromo-2′-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells, then treated with BPA or BSH. Immediately after reactor neutron beam irradiation, during which intratumor 10B concentrations were kept at levels similar to each other, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled quiescent (Q) and total (= P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU.ResultsThe CBE values were higher in Q cells and in the use of BPA than total cells and BSH, respectively. In addition, the higher the administered concentrations were, the smaller the CBE values became, with a clearer tendency in the use of BPA than BSH. The values for neutron capture agents that deliver into solid tumors more dependently on uptake capacity of tumor cells became more changeable.ConclusionTumor characteristics, such as micro-environmental heterogeneity, stochastic genetic or epigenetic changes, or hierarchical organization of tumor cells, are thought to partially influence on the value of CBE, meaning that the CBE value itself may be one of the indices showing the degree of tumor heterogeneity.

Deterministic Parsing Model of the Compound Biological Effectiveness (<i>CBE</i>) Factor for Intracellular <sup>10</sup>Boron Distribution in Boron Neutron Capture Therapy

Purpose: In defining the biological effects of the 10 B(n, α) 7 Li neutron capture reaction, we have previously developed a deterministic parsing model to determine the Compound Biological Effectiveness (CBE) factor in Borono-Phenyl-Alanine (BPA)-mediated Boron Neutron Capture Therapy (BNCT). In present paper, we demonstrate that the CBE factor is directly and unambiguously derivable by the new formula for any case of intracellular 10 Boron ( 10 B) distribution, which is founded on this model for tissues and tumor. Method: To determine the CBE factor, we derive the following new calculation formula founded on the deterministic parsing model with three constants, CBE0, F, n and the eigen value Nth/Nmax.

The radiobiological principles of boron neutron capture therapy: A critical review

The radiobiology of the dose components in a BNCT exposure is examined. The effect of exposure time in determining the biological effectiveness of γ-rays, due to the repair of sublethal damage, has been largely overlooked in the application of BNCT. Recoil protons from fast neutrons vary in their relative biological effectiveness (RBE) as a function of energy and tissue endpoint. Thus the energy spectrum of a beam will influence the RBE of this dose component. Protons from the neutron capture reaction in nitrogen have not been studied but in practice protons from nitrogen capture have been combined with the recoil proton contribution into a total proton dose. The relative biological effectiveness of the products of the neutron capture reaction in boron is derived from two factors, the RBE of the short range particles and the bio-distribution of boron, referred to collectively as the compound biological effectiveness factor. Caution is needed in the application of these factors for different normal tissues and tumors.