Microdosimetric Modeling of Biological Effectiveness for Boron Neutron Capture Therapy Considering Intra- and Intercellular Heterogeneity in 10B Distribution

We here propose a new model for estimating the biological effectiveness for boron neutron capture therapy (BNCT) considering intra- and intercellular heterogeneity in 10B distribution. The new model was developed from our previously established stochastic microdosimetric kinetic model that determines the surviving fraction of cells irradiated with any radiations. In the model, the probability density of the absorbed doses in microscopic scales is the fundamental physical index for characterizing the radiation fields. A new computational method was established to determine the probability density for application to BNCT using the Particle and Heavy Ion Transport code System PHITS. The parameters used in the model were determined from the measured surviving fraction of tumor cells administrated with two kinds of 10B compounds. The model quantitatively highlighted the indispensable need to consider the synergetic effect and the dose dependence of the biological effectiveness in the estimate of the therapeutic effect of BNCT. The model can predict the biological effectiveness of newly developed 10B compounds based on their intra- and intercellular distributions, and thus, it can play important roles not only in treatment planning but also in drug discovery research for future BNCT

Adverse effect of mild temperature hyperthermia combined with hexamethylenetetramine compared to its effect combined with tirapazamine in the treatment of solid tumors

This study aimed to assess the effect on solid tumors of mild temperature hyperthermia (MTH) combined with hexamethylenetetramine (HMTA) or tirapazamine (TPZ). Squamous cell carcinoma (SCC VII) tumor-bearing mice were continuously administered 5-bromo-2′-deoxyuridine (BrdU) to label intratumor proliferating (P) cells. Mice received HMTA or TPZ through intraperitoneal single or subcutaneous continuous administration, with or without MTH (40°C, 60 min), followed or not by γ-ray irradiation or cisplatin treatment. After HMTA or TPZ administration without γ-ray irradiation or cisplatin treatment, immediately after γ-ray irradiation, or 1 h after cisplatin treatment, the response of quiescent (Q) cells was assessed in terms of micronucleus frequency using immunofluorescence staining for BrdU. The response of the total (P + Q) tumor cells was determined based on a comparison with non-BrdU-treated tumors. Without MTH, HMTA and TPZ had a nearly equal radiosensitizing and cisplatin sensitivity-enhancing effect on both total and Q cells. With MTH, radio- and cisplatin-sensitizing effects by HMTA were reduced, particularly in the Q cells. In contrast, the enhancing effects of TPZ were increased, particularly in the Q cells. Continuous administration of HMTA and TPZ resulted in higher radio- and cisplatin-sensitizing effects than intraperitoneal single administration. In terms of tumor cytotoxicity as a whole, including Q cells, the administration of γ-ray irradiation or cisplatin treatment combined with continuous HMTA administration is promising, taking into account the clinical use of HMTA. However, MTH should not be combined with HMTA administration

Detection of γH2AX foci in mouse normal brain and brain tumor after boron neutron capture therapy

AimIn this study, we investigated γH2AX foci as markers of DSBs in normal brain and brain tumor tissue in mouse after BNCT.BackgroundBoron neutron capture therapy (BNCT) is a particle radiation therapy in combination of thermal neutron irradiation and boron compound that specifically accumulates in the tumor. 10B captures neutrons and produces an alpha (4He) particle and a recoiled lithium nucleus (7Li). These particles have the characteristics of extremely high linear energy transfer (LET) radiation and therefore have marked biological effects. High LET radiation causes severe DNA damage, DNA DSBs. As the high LET radiation induces complex DNA double strand breaks (DSBs), large proportions of DSBs are considered to remain unrepaired in comparison with exposure to sparsely ionizing radiation.Materials and methodsWe analyzed the number of γH2AX foci by immunohistochemistry 30[[ce:hsp sp="0.25"/]]min or 24[[ce:hsp sp="0.25"/]]h after neutron irradiation.ResultsIn both normal brain and brain tumor, γH2AX foci induced by 10B(n,α)7Li reaction remained 24[[ce:hsp sp="0.25"/]]h after neutron beam irradiation. In contrast, γH2AX foci produced by γ-ray irradiation at contaminated dose in BNCT disappeared 24[[ce:hsp sp="0.25"/]]h after irradiation in these tissues.ConclusionDSBs produced by 10B(n,α)7Li reaction are supposed to be too complex to repair for cells in normal brain and brain tumor tissue within 24[[ce:hsp sp="0.25"/]]h. These DSBs would be more difficult to repair than those by γ-ray. Excellent anti-tumor effect of BNCT may result from these unrepaired DSBs induced by 10B(n,α)7Li reaction

Usefulness of hexamethylenetetramine in combination with chemotherapy using free and pegylated liposomal doxorubicin in vivo, referring to the effect on quiescent cells

SCC VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all intratumor proliferating (P) cells. They received hexamethylenetetramine (HMTA) either once intraperitoneally or continuously subcutaneously together with chemotherapy using intraperitoneally administered free doxorubicin (DXR) or intravenously injected pegylated liposomal doxorubicin (PLD). One hour after the free DXR loading or 24 h after the PLD loading, the response of intratumor quiescent (Q) cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for BrdU. The response of the total (P + Q) tumor cell population was determined from the tumors not treated with BrdU. Encapsulation of DXR into pegylated liposomes significantly enhanced cytotoxicity, especially in Q cells. HMTA, especially when administered continuously, efficiently increased the sensitivity to DXR, particularly in Q cells. The increase in sensitivity on the continuous rather than single administration of HMTA was a little clearer in the total cell population than in Q cells. DXR's encapsulation into pegylated liposomes and combination with HMTA, particularly when administered continuously, apparently reduced the difference in sensitivity to free DXR between the total and Q cell populations. In terms of the tumor cell-killing effect as a whole, including Q cells, the encapsulation of DXR into pegylated liposomes and combination with HMTA, particularly through continuous administration, are very promising, taking into account that HMTA has been used clinically

固形腫瘍内静止期細胞の放射線感受性検出法の確立に関する研究

本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものである京都大学0048新制・課程博士医学博士甲第4740号医博第1241号新制||医||493(附属図書館)UT51-91-E111京都大学大学院医学研究科内科系専攻(主査)教授 杉山 武敏, 教授 内田 温士, 教授 阿部 光幸学位規則第5条第1項該当Kyoto UniversityDFA

Project 1 Analyzing Tumor Microenvironment and Exploiting its Characteristics in Search of Optimizing Cancer Therapy Including Neutron Capture Therapy (R2P1)

In case that corrections are made, an errata will be provided in the following webpage: https://www.rri.kyoto-u.ac.jp/PUB/report/PR/ProgRep2020/ProgRep2020.htmlPR1-1 Significance of combination with both continuous administration of hypoxic cytotoxin, tirapazamine and mild temperature hyperthermia in BNCT in terms of local tumor control and lung metastatic potential /S. Masunaga et al. (R2P1-1) [4]PR1-2 Development of Amino Acid Derivatives Containing ¹⁰B-Clusters for BNCT /A. Matsushita et al. (R2P1-2) [5]PR1-3 Proteolysis of a Histone Acetyl Reader Protein Induces Chemoresistance of Cancer Cells under Hypoxia by Inhibiting Cell Cycle Progression in S Phase /T. Haitani et al. (R2P1-3) [6]PR1-4 Cancer-Targeting Hyaluronic Acid/Carboranyl Pyrene Complex for Boron Neutron Capture Therapy /K. Yamana et al. (R2P1-6) [7]PR1-5 An evaluation of stratified mouse model and the response of tumor cells to BNCT /S. Imamichi et al. (R2P1-9) [8]PR1-6 Attempts to sensitize tumor cells by exploiting the tumor microenvironment /Y. Sanada et al. (R2P1-12) [9

I. ANNUAL SUMMARY OF EXPERIMENTAL RESEARCH ACTIVITIES. I-1. PROJECT RESEARCHES

In case that corrections are made, an errata will be provided in the following webpage: https://www.rri.kyoto-u.ac.jp/PUB/report/PR/ProgRep2019/ProgRep2019.htmlPR6-1 Effect of a change in reactor power on response of murine solid tumors in vivo, especially on that of quiescent tumor cells, in boron neutron capture therapy /S. Masunaga et al.(31P6-1) [63]PR6-2 Development of new amino acid-type boron carriers for BNCT /A. Matsushita et al.(31P6-2) [64]PR6-3 Molecular mechanism underlying HISP2-mediated radioresistance of hypoxic tumor cells /M. Kobayashi et al.(31P6-3) [65]PR6-4 OH radicals from the indirect actions of neutron beam induce cell killing /R. Hirayama et al.(31P6-4) [66]PR6-5 Intracellular Delivery of Membrane-fluidity Sensitive Boron Liposomes with Tumor-specific Cell Penetrating Peptides /S. Kasaoka et al.(31P6-5) [67]PR6-6 Preparation and Characterization of a Novel Bispecific Antibody That Targets Her2 and BSH for Boron Neutron Capture Therapy /T. Kanai et al.(31P6-6) [68]PR6-7 Development of novel BPA-Tirapazamine hybrid BNCT agent targeting hypoxic tumor cells /Y. Uto et al.(31P6-7) [69]PR6-8 The tumor invasion enhanced by the conditioned-medium after X-irradiation /H. Yasui et al.(31P6-8) [70]PR6-9 Analysis of the response of tumor tissue and cells to BNCT /S. Imamichi et al.(31P6-9) [71]PR6-10 The contribution of blood boron-neutron reaction to subcutaneous tumor growth suppression was equal to that of neutrons irradiation only group /K. Nakai et al.(31P6-10) [72]PR6-11 Cell killing effect of BNCT with novel boron compound SMA glucosamine complex /Y. Matsumoto et al.(31P6-11) [73]PR6-12 Attempts to sensitize tumor cells by exploiting the tumor microenvironment /Y. Sanada et al.(31P6-12) [74