Experimentally determined relative biological effectiveness of cyclotron-based epithermal neutrons designed for clinical BNCT: in vitro study.

A neutron beam for boron neutron capture therapy (BNCT) of deep-seated tumours is designed to maintain a high flux of epithermal neutrons, while keeping the thermal and fast neutron component as low as possible. These neutrons (thermal and fast) have a high relative biological effectiveness in comparison with high energy photon beams used for conventional X-ray radiotherapy. In the past, neutrons for the purpose of BNCT were generated using nuclear reactors.

Pharmacokinetic Study of C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model.

Background And Objective: Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells.

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.

HIF-1α affects sensitivity of murine squamous cell carcinoma to boron neutron capture therapy with BPA.

To examine whether hypoxia and Hif-1α affect sensitivity of murine squamous cell carcinoma cells to boron neutron capture therapy (BNCT). SCC VII and SCC VII Hif-1α-deficient mouse tumor cells were incubated under normoxic or hypoxic conditions, and cell survival after BNCT was assessed. The intracellular concentration of the B-carrier, boronophenylalanine-B (BPA), was estimated using an autoradiography technique.

Tumor-targeting hyaluronic acid/fluorescent carborane complex for boron neutron capture therapy.

In cancer therapeutics, boron neutron capture therapy (BNCT) requires a platform for selective and efficient B delivery into tumor tissues for a successful treatment. However, the use of carborane, a promising candidate with high boron content and biostability, has significant limitations in the biomedical field due to its poor water-solubility and tumor-selectivity. To overcome these hurdles, we present in this study a fluorescent nano complex, combining fluorescent carborane and sodium hyaluronate for high boron concentration and tumor-selectivity.

Effect of Rapamycin on the Radio-Sensitivity of Cultured Tumor Cells Following Boron Neutron Capture Reaction.

Background: Mammalian target of rapamycin (mTOR) signaling pathway has been implicated in multiple mechanisms of resistance to anticancer drugs and poor treatment outcomes in various human cancers. Meanwhile, clinical boron neutron capture therapy (BNCT) has been carried out for patients with malignant gliomas, melanomas, inoperable head and neck tumors and oral cancers. This study aimed to evaluate the effect of mTOR inhibition on radio-sensitivity of cultured tumor cells in BNCT, employing p-boronophenylalanine-B (BPA) as a B-carrier.

Synthesis and Evaluation of Dodecaboranethiol Containing Kojic Acid (KA-BSH) as a Novel Agent for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a form of tumor-cell selective particle irradiation using low-energy neutron irradiation of boron-10 (B) to produce high-linear energy transfer (LET) alpha particles and recoiling Li nuclei (B [n, alpha] Li) in tumor cells. Therefore, it is important to achieve the selective delivery of large amounts of B to tumor cells, with only small amounts of B to normal tissues. To develop practical materials utilizing B carriers, we designed and synthesized novel dodecaboranethiol (BSH)-containing kojic acid (KA-BSH).

An attempt to improve the therapeutic effect of boron neutron capture therapy using commonly employed 10B-carriers based on analytical studies on the correlation among quiescent tumor cell characteristics, tumor heterogeneity and cancer stemness.

Based on our previously published reports concerning the response of quiescent (Q) tumor cell populations to boron neutron capture therapy (BNCT), the heterogeneous microdistribution of 10B in tumors, which is influenced by the tumor microenvironment and the characteristics of the 10B delivery carriers, has been shown to limit the therapeutic effect of BNCT on local tumors. It was also clarified that the characteristics of 10B-carriers for BNCT and the type of combined treatment in BNCT can also affect the potential for distant lung metastases from treated local tumors. We reviewed the findings concerning the response of Q tumor cell populations to BNCT, mainly focusing on reports we have published so far, and we identified the mode of BNCT that currently offers the best therapeutic gain from the viewpoint of both controlling local tumor and suppressing the potential for distant lung metastasis.

Participation of TDP1 in the repair of formaldehyde-induced DNA-protein cross-links in chicken DT40 cells.

Proteins are covalently trapped on DNA to form DNA-protein cross-links (DPCs) when cells are exposed to DNA-damaging agents. Aldehyde compounds produce common types of DPCs that contain proteins in an undisrupted DNA strand. Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs topoisomerase 1 (TOPO1) that is trapped at the 3'-end of DNA.

Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential.

To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a B-carrier (-boronophenylalanine-B (BPA) or sodium mercaptoundecahydrododecaborate-B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH.

Effects of Status of Tumor Cells and Combined Treatment With Mild Hyperthermia, Wortmannin or Caffeine on Recovery From Radiation-Induced Damage.

Background: The aim of the study was to examine the dependency of status and the usefulness of mild hyperthermia (MHT) as an inhibitor of recovery from radiation-induced damage, referring to the response of quiescent (Q) tumor cell population.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant (SAS/) or with neo vector (SAS/) were injected subcutaneously into left hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells.

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-B (BPA) or sodium mercaptododecaborate-B (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.

DEPTH DISTRIBUTIONS OF RBE-WEIGHTED DOSE and PHOTON-ISOEFFECTIVE DOSE FOR BORON NEUTRON CAPTURE THERAPY.

Two types of dose were proposed for use in the treatment planning of boron neutron capture therapy (BNCT) for expressing its high relative biological effectiveness (RBE). On one hand, the RBE-weighted dose is the sum of the absorbed doses weighted by fixed RBE for each dose component of BNCT. On the other hand, photon-isoeffective dose is the photon dose to give the same biological effect calculated considering the dose dependence of RBE and the synergetic effect between different types of radiation.

Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats.

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl-closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats.

Proposal for determining absolute biological effectiveness of boron neutron capture therapy-the effect of 10B(n,α)7Li dose can be predicted from the nucleocytoplasmic ratio or the cell size.

The relationship between the radiation dose delivered to a tumor and its effect is not completely predictable. Uncertainty in the estimation of the boron concentration in a tumor, variation in the radiation sensitivity of the tumor cells, and the complexity of the interactions between the four types of radiation comprising the boron neutron capture therapy (BNCT) dose contribute to this uncertainty. We reanalyzed the data of our previous papers to investigate the variation in radiosensitivity of tumor cells to the 10B(n,α)7Li dose: the dose generated by the reaction of thermal neutrons and 10B, hereafter the 'boron-neutron dose'.

The Effect of Status on Radio-Sensitivity of Quiescent Tumor Cell Population Irradiated With γ-Rays at Various Dose Rates.

Background: The aim of the study was to clarify the effect of status of tumor cells on radio-sensitivity of solid tumors following γ-ray irradiation at various dose rates, referring to the response of intratumor quiescent (Q) cells.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant (SAS/) or with neo vector (SAS/) were injected subcutaneously into hind legs of nude mice. Tumor bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells.

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

We here propose a new model for estimating the biological effectiveness for boron neutron capture therapy (BNCT) considering intra- and intercellular heterogeneity in B 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.

Disruption of Hif-1α enhances cytotoxic effects of metformin in murine squamous cell carcinoma.

Purpose: In the present study, we investigated whether the disruption of the Hif-1α gene affects the sensitivity of SCC VII cells to metformin and also if metformin functions as a radiosensitizer using murine squamous cell carcinoma (SCC VII) cells.

Materials And Methods: Cultured SCC VII and SCC VII Hif-1α-deficient cells were incubated with metformin under glucose-free and/or hypoxia-mimetic conditions and cell viabilities were measured. Tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating cells.

Effect of Tirapazamine, Metformin or Mild Hyperthermia on Recovery From Radiation-Induced Damage in Pimonidazole-Unlabeled Quiescent Tumor Cells.

Background: The aim of the study was to examine the effect of tirapazamine (TPZ) on recovery from radiation-induced damage in pimonidazole-unlabeled quiescent (Q) tumor cells compared with that of metformin (Met) or mild temperature hyperthermia (MTH).

Methods: Proliferating (P) cells in EL4 tumors were labeled by continuous 5-bromo-2'-deoxyuridine (BrdU) administration. Tumors received γ-rays at 1 h after pimonidazole administration followed by Met or TPZ treatment or MTH.

Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells.

Metformin is a biguanide drug that is widely used in the treatment of diabetes. Epidemiological studies have indicated that metformin exhibits anti-cancer activity. However, the molecular mechanisms underlying this activity currently remain unclear.

Selective boron delivery by intra-arterial injection of BSH-WOW emulsion in hepatic cancer model for neutron capture therapy.

Objective: Boron neutron-capture therapy (BNCT) has been used to inhibit the growth of various types of cancers. In this study, we developed a BSH-entrapped water-in-oil-in-water (WOW) emulsion, evaluated it as a selective boron carrier for the possible application of BNCT in hepatocellular carcinoma treatment.

Methods: We prepared the BSH-entrapped WOW emulsion using double emulsification technique and then evaluated the delivery efficacy by performing biodistribution experiment on VX-2 rabbit hepatic tumour model with comparison to iodized poppy-seed oil mix conventional emulsion.