boron and Glioma

Systems biology approach, carried out with high-throughput omics technologies, has become a fundamental aspect of the study of complex diseases like cancer. It can molecularly characterize subjects, physiopathological conditions, and interactions, allowing a precise description, to reach personalized medicine. In particular, proteomics, typically performed with liquid chromatography coupled to mass spectrometry, is a powerful tool for systems biology, giving the possibility to perform diagnosis, patient stratification, and prediction of therapy effects. Boron Neutron Capture Therapy (BNCT) is a selective antitumoral radiotherapy based on a nuclear reaction that occurs when Boron-10 (

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Glioma; Humans; Systems Biology

In an investigation by the Swedish Cancer Society, an expert group described the present status, critical issues and future aspects and potentials for each of nine major areas of radiation therapy research. This report deals with radiation therapy using activation of stable nuclides.

Topics: Boron; Gadolinium; Glioma; Humans; Isotopes; Melanoma; Neoplasms; Neutron Capture Therapy

The stable isotope 10B has a peculiarly marked avidity to capture slow neutrons whereupon it disintegrates into a lithium and a helium atom. These give up the 2.4 MeV of disintegration energy which they share within 5 and 9 microns of the 10B atom respectively. This means that the cell closest to the 10B atom bears the brunt of its atomic explosion. The objective of the tumor therapist is to find a carrier molecule for the boron atom which will concentrate in the tumor. Although a number of investigators saw the peculiar advantage of this selective tactic to achieve destruction of a species of unwanted cells, no success in animal studies was achieved until 1950. Sweet and colleagues found that the capillary blood-brain barrier keeps many substances out of the normal brain but that the gliomas had much less of such a barrier. He, Brownell, Soloway and Hatanaka in Boston together with Farr. Godwin, Robertson, Stickley. Konikowski and others at the Brookhaven. National Laboratory worked partially in collaboration and partly independently. We irradiated at 3 nuclear reactors several series of glioma patients with no long-term remission, much less a cure being achieved. Hatanaka on his return to Japan kept BNCT alive by treating a total of 140 patients with various brain tumors. Beginning in 1972, Mishima and colleagues have achieved useful concentrations of 10B-borono-phenylalanine, an analogue of the melanin precursor tyrosine, for BNCT of melanomas.

Topics: Blood-Brain Barrier; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Glioma; Humans; Isotopes; Nuclear Reactors

Both fast neutron radiotherapy and boron neutron capture therapy have been investigated as new radiation treatment techniques for patients with malignant gliomas. While each of these techniques individually has shown the potential for pathological eradication of malignant glioma, to date neither has evolved into an accepted, improved method of treatment. We have recently begun a research program investigating the feasibility of combining the benefits of both types of therapy. As a fast neutron beam penetrates tissue some of the particles are degraded to thermal energies. These can be captured by 10B or other suitable isotopes resulting in a highly-localized release of additional energy during a course of fast neutron radiotherapy. In this article we will review the rationale for such an approach, and review the underlying physics as well as in vitro, in vivo, and early human studies testing its feasibility. If appropriate carrier agents can be found that preferentially-localize in tumor cells, this approach ena be applied to many different tumor systems.

Topics: Animals; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Line; Cell Survival; Cricetinae; Cricetulus; Fast Neutrons; Feasibility Studies; Glioma; Humans; Isotopes; Rats

This paper reviews the development of boron neutron capture therapy (BNCT) and describes the design and dosimetry of an intermediate energy neutron beam, developed at the Harwell Laboratory, principally for BNCT research. Boron neutron capture therapy is a technique for the treatment of gliomas (a fatal form of brain tumour). The technique involves preferentially attaching 10B atoms to tumour cells and irradiating them with thermal neutrons. The thermal neutron capture products of 10B are short range and highly damaging, so they kill the tumour cells, but healthy tissue is relatively undamaged. Early trials required extensive neurosurgery to exposure the tumour to the thermal neutrons used and were unsuccessful. It is thought that intermediate-energy neutrons will overcome many of the problems encountered in the early trials, because they have greater penetration prior to thermalization, so that surgery will not be required. An intermediate-energy neutron beam has been developed at the Harwell Laboratory for research into BNCT. Neutrons from the core of a high-flux nuclear reactor are filtered with a combination of iron, aluminium and sulphur. Dosimetry measurements have been made to determine the neutron and gamma-ray characteristics of this beam, and to monitor them throughout the four cycles used for BNCT research. The beam is of high intensity (approximately 2 x 10(7) neutrons cm-2 s-1, equivalent to a neutron kerma rate in water of 205 mGy h-1) and nearly monoenergetic (93% of the neutrons have energies approximately 24 keV, corresponding to 79% of the neutron kerma rate).

Topics: Boron; Brain Neoplasms; Glioma; Humans; Isotopes; Neutrons; Radiotherapy; Radiotherapy Dosage

If a certain means enables a selective loading of tumor cells with a stable isotope of boron-10, the tumor tissue can be selectively destroyed when the tumor-containing organ is exposed to slow neutron beams as the result of intracellular heavy particle radiations which arise from boron-10 atoms in the neutron capture reactions. An early clinical trial in the U.S.A. was discontinued after the 1953-1961 series, but the clinical trial resumed in Japan in 1968 has so far treated almost 90 patients with malignant brain tumors. The longest surviving patient has lived 16 years, and two others have lived 10 years. A median survival of 2 years was obtained with 12 patients with grade III - IV gliomas which had been within 6 cm from the cortical surface. This success has caused a reassessment of this therapy throughout the world, and there is an internationally concerted effort is going on in most countries with advanced technology. Application of this therapy to other incurable cancers, such as those of the liver, pancreas, skin and even of the bone-marrow is being sought.

Topics: Animals; Boron; Brain Neoplasms; Glioma; Humans; Liver Neoplasms, Experimental; Neutrons; Nuclear Reactors

Topics: Animals; Autoradiography; Bone Neoplasms; Boron; Brain; Brain Neoplasms; Carcinoma, Ehrlich Tumor; Glioma; Humans; Hyperthermia, Induced; Isotopes; Melanoma; Meningeal Neoplasms; Meningioma; Neutrons; Nuclear Reactors; Osteosarcoma; Radiotherapy Dosage; Sarcoma; Tomography, X-Ray Computed

Topics: Adjuvants, Immunologic; Adult; Boron; Brain Neoplasms; Bromodeoxyuridine; Cell Cycle; Cell Division; Combined Modality Therapy; Female; Glioma; Humans; Interferons; Isotopes

Topics: Animals; Boron; Brain Neoplasms; Glioma; Humans; Immunoglobulins; Japan; Massachusetts; Neoplasms, Experimental; Neutrons; Radiation Dosage; Radioisotopes; Radiotherapy; Rats

Topics: Animals; Boron; Brain Neoplasms; Cadmium; Cerebellar Neoplasms; Child; Ependymoma; Female; Glioma; Humans; Lithium; Lymphoma; Mammary Neoplasms, Experimental; Mice; Neoplasms, Experimental; Radioisotopes; Rhabdomyosarcoma; Sarcoma; Sarcoma, Experimental

Topics: Adult; Borohydrides; Boron; Brain Neoplasms; Clinical Trials as Topic; Glioma; Humans; Isotopes; Neutrons; Prospective Studies; Sulfhydryl Compounds

Proton boron capture therapy (PBCT) has emerged from particle acceleration research for enhancing the biological effectiveness of proton therapy. The mechanism responsible for the dose increase was supposed to be related to proton-boron fusion reactions (

Topics: Boron; Glioma; Humans; Male; Proton Therapy; Protons; Sodium

Boron neutron capture therapy (BNCT) is a high-LET particle radiotherapy clinically tested for treating malignant gliomas. Boronophenylalanine (BPA), a boron-containing phenylalanine derivative, is selectively transported into tumor cells by amino acid transporters, making it an ideal agent for BNCT. In this study, we investigated whether the amino acid 5-aminolevulinic acid (ALA) could sensitize glioma stem cells (GSCs) to BNCT by enhancing the uptake of BPA. Using human and mouse GSC lines, pre-incubation with ALA increased the intracellular accumulation of BPA dose-dependent. We also conducted in vivo experiments by intracerebrally implanting HGG13 cells in mice and administering ALA orally 24 h before BPA administration (ALA + BPA-BNCT). The ALA preloading group increased the tumor boron concentration and improved the tumor/blood boron concentration ratio, resulting in improved survival compared to the BPA-BNCT group. Furthermore, we found that the expression of amino acid transporters was upregulated following ALA treatment both in vitro and in vivo, particularly for ATB

Topics: Aminolevulinic Acid; Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Glioma; Humans; Mice; Neoplastic Stem Cells

Introduction Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. Methods and Results In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 h after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 h after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 h after MID-AC administration. Conclusion MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.

Topics: Albumins; Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Glioma; Humans; Maleimides; Rats; Tissue Distribution

The synthesis of d-glucoheptose derivative containing a boronic moiety is described herein. Starting from benzyl 6,7-dideoxy-2,3,4-tri-O-benzyl-β-d-gluco-ept-6-enopyranoside, the introduction of the boronic acid was performed through a metathesis reaction by using MIDA vinyl boronic acid and the 2nd generation Grubbs catalyst. Hydrogenation led to the final product in only two reaction steps. This new sugar-containing boronic acid in the skeleton could mimic carbohydrate behavior and follow the glucose uptake in living cells. The in vitro toxicity tests performed in fibroblasts and glioma tumor cell lines showed minimal toxicity. Boron uptake measured using ICP-MS was minimal in fibroblasts, while in glioma cells showed a value of 6 ng of total boron accumulation per mg of cells, implying that compound 1a is able to accumulate selectively in the tumor tissues compared to normal.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Boronic Acids; Carbohydrates; Cell Line, Tumor; Glioma; Glucose; Humans

Nanotechnology has revolutionized drug delivery in cancer treatment. In this study, novel efficient pH-responsive boron phenylalanine (BPA) targeted nanoparticles (NPs) based on ionic liquid modified chitosan have been introduced for selective mitoxantrone (MTO) delivery to the U87MG glioma cells. Urocanic acid (UA) and imidazolium (Im) based ionic liquids were used for structural modification simultaneously. The NPs were prepared by ionic gelation and fully characterized; the pH-responding and swelling index of NPs were studied carefully. The drug release was studied at a pH of 5.5 in comparison to the neutral state. Also, the cytotoxicity of loaded NPs was evaluated on U87MG glial cells, and cellular uptake was studied. The NPs were smaller than 250 nm, with a spherical pattern and acceptable uniformity with a zeta potential around +20 mV. The loading efficacy was about 85%, and most of the loaded MTO released at a pH of 5.5 after 48 h with a swelling-controlled mechanism. The NPs showed a relatively lower IC

Topics: Antineoplastic Agents; Boron; Cell Line, Tumor; Chitosan; Glioma; Humans; Microscopy, Electron, Transmission; Mitoxantrone; Nanoparticle Drug Delivery System; Nanoparticles; Phenylalanine

Topics: Animals; Apoptosis; Boron; Boron Neutron Capture Therapy; Cell Cycle; Cell Line; Drug Carriers; Endocytosis; Fluorescent Dyes; Glioma; Humans; Hydrophobic and Hydrophilic Interactions; Mice; Neoplasms, Experimental; Optical Imaging; Particle Size; Surface Properties

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. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)-a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21-24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26-36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25-37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28-40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Cell Line, Tumor; Cell Transformation, Neoplastic; Folate Receptors, GPI-Anchored; Glioma; Humans; Male; Molecular Targeted Therapy; Rats; Tissue Distribution

Boron neutron capture therapy (BNCT) is a promising radiotherapy for treating glioblastoma multiforme (GBM). However, the penetration of drugs (e.g., sodium borocaptate and BSH) for BNCT into brain tumors is limited by cerebral vesicular protective structures, the blood-brain barrier, and the blood-brain tumor barrier (BTB). Although BSH has been reported to be selectively taken up by tumors, it is rapidly excreted from the body and cannot achieve a high tumor-to-normal brain ratio (T/N ratio) and tumor-to-blood ratio (T/B ratio). Despite the development of large-molecular weight boron compounds, such as polymers and nanoparticles, to enhance the permeation and retention effect, their effects remain insufficient for clinical use. To improve the efficiency of boron delivery to the tumor site, we propose combinations of self-assembled boron-containing polyanion [polyethylene glycol- b-poly(( closo-dodecaboranyl)thiomethylstyrene) (PEG- b-PMBSH)] nanoparticles (295 ± 2.3 nm in aqueous media) coupled with cationic microbubble (B-MB)-assisted focused ultrasound (FUS) treatment. Upon FUS sonication (frequency = 1 MHz, pressure = 0.3-0.7 MPa, duty cycle = 0.5%, sonication = 1 min), B-MBs can simultaneously achieve safe BTB opening and boron drug delivery into tumor tissue. Compared with the MBs of the PEG- b-PMBSH mixture group (B + MBs), B-MBs showed 3- and 2.3-fold improvements in the T/N (4.4 ± 1.4 vs 1.3 ± 0.1) and T/B ratios (1.4 ± 0.6 vs 0.1 ± 0.1), respectively, after 4 min of FUS sonication. The spatial distribution of PEG- b-PMBSH was also improved by the complex of PEG- b-PMBSH with MBs. The findings presented herein, in combination with the expanding clinical application of FUS, may improve BNCT and treatment of GBM.

Topics: Animals; Blood-Brain Barrier; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Glioma; Humans; Lipid Bilayers; Male; Mice; Mice, Inbred C57BL; Microbubbles; Nanoparticles; Polymers; Sonication; Tissue Distribution

New 1,7-closo-carboranylanilinoquinazoline hybrids have been identified as EGFR inhibitors, one of them with higher affinity than the parent compound erlotinib. The comparative docking analysis with compounds bearing bioisoster-substructures, demonstrated the relevance of the 3D aromatic-boron-rich moiety for interacting into the EGFR ATP binding region. The capability to accumulate in glioma cells, the ability to cross the blood-brain barrier and the stability on simulated biological conditions, render these molecules as lead compounds for further structural modifications to obtain dual action drugs to treat glioblastoma.

Topics: Aniline Compounds; Blood-Brain Barrier; Boron; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Glioma; Humans; Protein Kinase Inhibitors; Quinazolines

Amino acid-based tracers have been extensively investigated for positron emission tomography (PET) imaging of brain tumors, and

Topics: Boron; Brain Neoplasms; Carbon Radioisotopes; Glioma; Humans; Methionine; Positron-Emission Tomography

Glioblastoma, a malignant brain tumor with poor disease outcomes, is managed in modern medicine by multimodality therapy. Boron neutron capture therapy (BNCT) is an encouraging treatment under clinical investigation. In malignant cells, BNCT consists of two major factors: neutron radiation and boron uptake. To increase boron uptake in cells, we created a mercapto-closo-undecahydrododecaborate ([B12HnSH](2-)2Na(+), BSH) fused with a short arginine peptide (1R, 2R, 3R) and checked cellular uptake in vitro and in vivo. In a mouse brain tumor model, only BSH with at least three arginine domains could penetrate cell membranes of glioma cells in vitro and in vivo. Furthermore, to monitor the pharmacokinetic properties of these agents in vivo, we fused BSH and BSH-3R with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); DOTA is a metal chelating agent for labeling positron emission tomography (PET) probe with (64)Cu. We administered BSH-DOTA-(64)Cu and BSH-3R-DOTA-(64)Cu to the tumor model through a mouse tail vein and determined the drugs' pharmacokinetics by PET imaging. BSH-3R showed a high uptake in the tumor area on PET imaging. We concluded that BSH-3R is the ideal boron compound for clinical use during BNCT and that in developing this compound for clinical use, the BSH-3R PET probe is essential for pharmacokinetic imaging.

Topics: Animals; Arginine; Boron; Boron Neutron Capture Therapy; Boronic Acids; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Copper; Disease Models, Animal; Drug Delivery Systems; Female; Glioma; Heterocyclic Compounds, 1-Ring; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Oligopeptides; Peptides; Positron-Emission Tomography; Tomography, X-Ray Computed

Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells.. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression.. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins.. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.

Topics: Apoptosis; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Cycle; Cell Cycle Checkpoints; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Glioma; Humans; Mitochondria; Neutrons; Recurrence; Stem Cells; Time Factors

To plan the optimal BNCT for patients with malignant cerebral glioma, estimation of the ratio of boron concentration in tumor tissue against that in the surrounding normal brain (T/N ratio of boron) is important. We report a positron emission tomography (PET) imaging method to estimate T/N ratio of tissue boron concentration based on pharmacokinetic analysis of amino acid probes.. Twelve patients with cerebral malignant glioma underwent 60 min dynamic PET scanning of brain after bolus injection of (18)F-borono-phenyl-alanine (FBPA) with timed arterial blood sampling. Using kinetic parameter obtained by this scan, T/N ratio of boron concentration elicited by one-hour constant infusion of BPA, as performed in BNCT, was simulated on Runge-Kutta algorithm. (11)C-methionine (MET) PET scan, which is commonly used in worldwide PET center as brain tumor imaging tool, was also performed on the same day to compare the image characteristics of FBPA and that of MET.. PET glioma images obtained with FBPA and MET are almost identical in all patients by visual inspection. Estimated T/N ratio of tissue boron concentration after one-hour constant infusion of BPA, T/N ratio of FBPA on static condition, and T/N ratio of MET on static condition showed significant linear correlation between each other.. T/N ratio of boron concentration that is obtained by constant infusion of BPA during BNCT can be estimated by FBPA PET scan. This ratio can also be estimated by MET-PET imaging. As MET-PET study is available in many clinical PET center, selection of candidates for BNCT may be possible by MET-PET images. Accurate planning of BNCT may be performed by static images of FBPA PET. Use of PET imaging with amino acid probes may contribute very much to establish an appropriate application of BNCT for patients with malignant glioma.

Topics: Algorithms; Astrocytoma; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Carbon Radioisotopes; Glioblastoma; Glioma; Humans; Methionine; Phenylalanine; Positron-Emission Tomography; Radiation-Sensitizing Agents; Radiotherapy Planning, Computer-Assisted

The purpose of the present study was to evaluate the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98(EGFR)) or mutant receptors(F98(npEGFRvIII)).. A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats. Biodistribution studies were carried out by administering (125)I-labeled bioconjugates via convection-enhanced delivery (CED), and for therapy studies, nonradiolabeled bioconjugates were used for BNCT. This was carried out 14 days after tumor implantation and 24 h after CED at the Massachusetts Institute of Technology nuclear reactor.. Following CED of a mixture of (125)I-BD-C225 and (125)I-BD-L8A4 to rats bearing composite tumors, 61.4% of the injected dose per gram (ID/g) was localized in the tumor compared with 30.8% ID/g for (125)I-BD-L8A4 and 34.7% ID/g for (125)I-BD-C225 alone. The corresponding calculated tumor boron values were 24.4 mug/g for rats that received both mAbs, and 12.3 and 13.8 mug/g, respectively, for BD-L8A4 or BD-C225 alone. The mean survival time of animals bearing composite tumors, which received both mAbs, was 55 days (P < 0.0001) compared with 36 days for BD-L8A4 and 38 days for BD-C225 alone, which were not significantly different from irradiated controls.. Both EGFRvIII and wild-type EGFR tumor cell populations must be targeted using a combination of BD-cetuximab and BD-L8A4. Although in vitro C225 recognized both receptors, in vivo it was incapable of delivering the requisite amount of (10)B for BNCT of EGFRvIII-expressing gliomas.

Topics: Animals; Antibodies, Monoclonal; Binding Sites, Antibody; Boron; Brain Neoplasms; Disease Models, Animal; ErbB Receptors; Glioma

The efficiency of boron neutron capture therapy (BNCT) for malignant gliomas depends on the selective and absolute accumulation of (10)B atoms in tumor tissues. Only two boron compounds, BPA and BSH, currently can be used clinically. However, the detailed distributions of these compounds have not been determined. Here we used secondary ion mass spectrometry (SIMS) to determine the histological distribution of (10)B atoms derived from the boron compounds BSH and BPA. C6 tumor-bearing rats were given 500 mg/kg of BPA or 100 mg/kg of BSH intraperitoneally; 2.5 h later, their brains were sectioned and subjected to SIMS. In the main tumor mass, BPA accumulated heterogeneously, while BSH accumulated homogeneously. In the peritumoral area, both BPA and BSH accumulated measurably. Interestingly, in this area, BSH accumulated distinctively in a diffuse manner even 800 microm distant from the interface between the main tumor and normal brain. In the contralateral brain, BPA accumulated measurably, while BSH did not. In conclusion, both BPA and BSH each have advantages and disadvantages. These compounds are considered to be essential as boron delivery agents independently for clinical BNCT. There is some rationale for the simultaneous use of both compounds in clinical BNCT for malignant gliomas.

Topics: Animals; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain; Brain Neoplasms; Cell Line, Tumor; Glioma; Ions; Male; Mass Spectrometry; Neoplasm Transplantation; Rats; Rats, Wistar; Time Factors

Boron neutron capture therapy (BNCT) and magnetic resonance imaging (MRI) are quite attractive techniques for treatment and diagnosis of cancer, respectively. In order to develop practical materials utilizing both for BNCT and MRI, fluorinated p-boronophenylalanines and their alcohol derivatives had already been designed and synthesized. In the present paper the cytotoxicity, the incorporated amount into cancer cells, and the tumor cell killing effects of these compounds were elucidated to evaluate their usefulness as a boron carrier.

Topics: Animals; Antineoplastic Agents; Boron; Boron Compounds; Cell Survival; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Glioma; Hydrocarbons, Fluorinated; Ion Transport; Models, Biological; Phenylalanine; Rats; Solubility; Tumor Cells, Cultured

A simple model has been developed for predicting radiobiological effectiveness of the neutron capture reaction in boron neutron capture therapy. This model was derived from the relationship between the cell survival from the boron capture reaction, the intracellular boron concentration, and the thermal neutron fluence. We found that the cell-killing effect of the boron capture reaction was well described using a power function of the intracellular boron concentration. Hence the relationship between cell survival from the boron capture reaction, intracellular boron concentration, and the thermal neutron fluence could be determined using a simple mathematical equation. We consider that our current approach is more appropriate and realistic than the conventional theoretical mathematical model used to estimate the radiobiological effectiveness of the neutron capture reaction in boron neutron capture therapy.

Topics: Animals; Boron; Cell Line, Tumor; Cell Survival; Computer Simulation; Dose-Response Relationship, Radiation; Glioma; Isotopes; Lithium; Models, Biological; Radiography; Radiometry; Radiotherapy Dosage; Radiotherapy, Computer-Assisted; Rats; Rats, Inbred F344; Relative Biological Effectiveness

Cetuximab (IMC-C225) is a monoclonal antibody directed against both the wild-type and mutant vIII isoform of the epidermal growth factor receptor (EGFR). The purpose of the present study was to evaluate the monoclonal antibody (MoAb), cetuximab, as a boron delivery agent for neutron capture therapy (NCT) of brain tumors. Twenty-four hours following intratumoral (i.t.) administration of boronated cetuximab (C225-G5-B(1100)), the mean boron concentration in rats bearing either F98(EGFR) or F98(WT) gliomas were 92.3+/-23.3 microg/g and 36.5+/-18.8 microg/g, respectively. In contrast, the uptake of boronated dendrimer (G5-B(1000)) was 6.7+/-3.6 microg/g. Based on its favorable in vivo uptake, C225-G5-B(1100) was evaluated as a delivery agent for BNCT in F98(EGFR) glioma bearing rats. The mean survival time (MST) of rats that received C225-G5-B(1100), administered by convection enhanced delivery (CED), was 45+/-3d compared to 25+/-3d for untreated control animals. A further enhancement in MST to >59d was obtained by administering C225-G5-B(1100) in combination with i.v. boronophenylalanine (BPA). These data are the first to demonstrate the efficacy of a boronated MoAb for BNCT of an intracerebral (i.c.) glioma and are paradigmatic for future studies using a combination of boronated MoAbs and low molecular weight delivery agents.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cetuximab; Drug Delivery Systems; Epidermal Growth Factor; ErbB Receptors; Glioma; Iodine Radioisotopes; Mutation; Rats; Rats, Inbred F344

It has been shown that human malignant glioma tumours consist of several subpopulations of tumour cells. Due to heterogeneity and different degrees of vascularisation cell subpopulations possess varying resistance to chemo- or radiation therapy. Therefore, therapy is dependent on the ability to specifically target a tumour cell. Boron neutron capture therapy (BNCT) is a bimodal method, in radiation therapy, taking advantage of the ability of the stable isotope boron-10 to capture neutrons. It results in disintegration products depositing large amounts of energy within a short length, approximately one cell diameter. Thereby, selective irradiation of a target cell may be accomplished if a sufficient amount of boron has been accumulated and hence the cell-associated boron concentration is of critical importance. The accumulation of boron, boronophenylalanine (BPA), was investigated in two human glioma cell subpopulations and a human fibroblast cell line in vitro. The cells were incubated at low boron concentrations (0-5 microg B/ml). Oil filtration was then used for separation of extracellular and cell-associated boron. Inductively coupled plasma atomic emission spectroscopy (ICP-AES) was used for boron determination. Significant (P < 0.05) differences in accumulation ratio (relation between cell-associated and extracellular boron concentration) between human malignant glioma cell lines were found. Human fibroblasts, used to represent normal cells, showed a growth-dependent uptake and a lower accumulation ratio than the glioma cells. Our findings indicate that BPA concentration, incubation time and differences in boron uptake between cell subpopulations should be considered in BNCT.

Topics: Boranes; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Line; Cell Line, Tumor; Fibroblasts; Glioblastoma; Glioma; Humans; Phenylalanine

Mercaptoundecahydrododecaborate (Na2B12H111SH, sodium borocaptate or 'BSH') has been used clinically as a boron compound for boron neutron capture therapy (BNCT) in patients with malignant glioma in Japan and Europe. Boron-10 is known to accumulate selectively only in brain tumor cells. This work was aimed to clarify the subcellular biodistribution of BSH in a rat glioma model using immunohistochemical approach. Wistar rats were used for this experiment. An intracerebral injection of 5.0 x 10(6) C6 glioma cells was introduced into the region of cerebral hemisphere. Fifty milligrams of "'B/kg BSH was infused intravenously two weeks after implantation. Host rats were divided into six groups according to the sampling time: 1, 4, 8, 16, 24 and 48 h after the start of BSH infusion. Immunohistochemical study was carried out using anti-BSH antibody. Boron was already found in a whole cell 1 h after BSH infusion, and then seemed to collect in a cell nuclei around 8-16 h after infusion. It was still recognized in tumor cell 48 h after infusion. This study supports the following hypothesis on selective boron uptake in a tumor. BSH can pass through the disrupted blood-brain barrier (BBB) easily and can come in contact with tumor cells; there, BSH can bind on the extracellular surface of plasma membrane to choline residues. After binding to the plasma membrane, boron with choline residues may be internalized into the cell by endocytic pathways and eventually travel to cell nuclei, and then stay there for a long time.

Topics: Animals; Borohydrides; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Glioma; Immunohistochemistry; Infusions, Intravenous; Injections, Intraventricular; Neoplasm Transplantation; Rats; Rats, Wistar; Subcellular Fractions; Sulfhydryl Compounds; Time Factors; Tissue Distribution

A new boronated porphyrin compound (STA-BX909) was developed as a possible agent for boron neutron capture therapy. The boron concentration was measured by an in vivo rat experimental brain tumor model and an in vitro cell culture study. This agent was compared to sodium borocaptate (BSH) which has been used in clinical trials of boron neutron capture therapy. In the 9L rat brain tumor model, STA-BX909 achieved a higher boron tumor/blood ratio 24 h after injection in comparison to BSH. A boron concentration study in cultured glioma cell lines (U-251, U-87, 9L) demonstrated an increased boron concentration as a function of exposure time to STA-BX909, while the boron concentration remained stable with increasing exposure time to BSH. Use of a colony forming assay with thermal neutron irradiation revealed more cytotoxicity with STA-BX909 than BSH when the same concentration of 10B was administered. We concluded that STA-BX909 may be an effective drug for use in boron neutron capture therapy and that it merits further investigation.

Topics: Animals; Borohydrides; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Survival; Glioma; Metalloporphyrins; Neoplasm Transplantation; Rats; Rats, Inbred F344; Sulfhydryl Compounds; Tissue Distribution; Tumor Cells, Cultured; Tumor Stem Cell Assay

The interaction of mercaptoundecahydrododecaborate (B12H11SH2-, BSH) with phosphatidylcholine was investigated in this study in order to illuminate possible uptake mechanisms of BSH in tumor cells. BSH has been used clinically in Japan as a boron containing agent in patients with malignant brain tumors for boron neutron capture therapy (BNCT). After infusion, BSH accumulates selectively in tumor tissue. Little is known for the mechanism of boron uptake to tumor cells. Fourier transform infrared (FTIR) spectrometry was used to quantify BSH (at wavenumber 2490 cm-1) and phosphatidylcholine (at wavenumber 2850-2970 cm-1). After extraction into carbon tetrachloride (CCl4), we could find an absorbance maximum at 2490 cm-1 as a B-H band in the mixture of BSH with phosphatidylcholine, which is attributed to a BSH-phosphatidylcholine complex, which could dissolve well in CCl4. The molar ratio of BSH to phosphatidylcholine in the CCl4 solution was at most one mole of BSH to two moles of phosphatidylcholine independent of the excess BSH. The doubly negatively charged BSH can interact with two phosphatidylcholine molecules through their singly positively charged choline residues. These ion pairs could be responsible for membrane binding and penetration, and for cell internalization.

Topics: Borohydrides; Boron; Calibration; Glioma; Humans; Neutron Capture Therapy; Phosphatidylcholines; Spectroscopy, Fourier Transform Infrared; Sulfhydryl Compounds

Determination of tumor boron-10 (10B) levels is required for accurate neutron dosimetry during boron neutron capture therapy. We assessed a new method for quantitative measurement of boronated drug uptake in high-grade gliomas. This method uses positron emission tomography (PET) with fluorine-18-labeled L-fluoroborono-phenylalanine (L-18F-10B-FBPA), which was synthesized as an analogue of L-boronophenylalanine. We studied the accumulation of L-18F-10B-FBPA by PET in patients with high-grade gliomas. Dynamic PET studies of brain tumors revealed that L-18F-10B-FBPA accumulated gradually after bolus injection, and the value of PET activity divided by the integrated plasma activity reached a constant level 42 min after injection, which was defined as the incorporation constant (Ic*). This constant reflected the appropriate L-18F-10B-FBPA accumulation in tumor tissue. Based on the Ic* constant, the methods for estimating tumor 10B concentration were devised. With this method, the estimated values of 10B concentration in gliomas were very close to the 10B levels in surgical specimens. This method was based solely on PET and can potentially provide data that would assist in the selection of patients for future treatment with boron neutron capture therapy after surgical resection of their brain tumors.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Fluorine Radioisotopes; Glioma; Humans; Isotopes; Phenylalanine; Radiation-Sensitizing Agents; Tomography, Emission-Computed

Based on pharmacokinetic findings of fluorine-18-labeled L-fluoroboronophenylalanine by positron emission tomography (PET), methods for estimating tumor 10B concentration were devised. In clinical practice of boron neutron capture therapy (BNCT) for high-grade gliomas, a large amount of L-boronophenylalanine (L-10B-BPA)-fructose solution is used. Under these conditions, a slow i.v. infusion of L-10B-BPA-fructose solution should be performed for BNCT; therefore, the changes over time in 10B concentration in the target tissue were estimated by convoluting the actual time course of changes in plasma 10B concentration with a PET-based weight function including the proper rate constants [K1 (ml/g/min), k2 (min(-1)), k3 (min(-1)), and k4 (min(-1))]. With this method, the estimated values of 10B concentration in gliomas were very close to the 10B levels in surgical specimens. This demonstrated the similarity in pharmacokinetics between fluorine-18-labeled L-fluoroboronophenylalanine and L-10B-BPA. This method, using the appropriate rate constant, permits the determination of tumor 10B concentration and is widely suitable for clinical BNCT, because the averaged PET data are enough to use in future patients without individual PET study.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Fluorine Radioisotopes; Glioma; Humans; Isotopes; Mathematical Computing; Phenylalanine; Radiation-Sensitizing Agents; Tomography, Emission-Computed

We evaluated retrospectively the pharmacokinetics and boron uptake of BSH (mercaptoundecahydrododecarborate) for Boron Neutron Capture Therapy (BNCT) in 123 patients undergoing craniotomy for intracranial tumors. The pharmacokinetics revealed that BSH could move easily from blood to the peripheral organs; it was retained there and elimination was very slow. BSH after intra-arterial infusion (i.a.) was found to move into the peripheral organs more easily than after intra-venous (i.v.) infusion. In patients with malignant glioma, the average values of boron concentration in tumor and the tumor to blood ratio (T/B ratio) after i.a. infusion were 26.8 +/- 19.5 micrograms/g (range, 6.1-104.7 micrograms/g) and 1.77 +/- 1.30 (range, 0.47-6.65) respectively. On the other hand, after i.v. infusion the values were 20.9 +/- 12.2 micrograms/g (range, 7.0-39.7 micrograms/g) and 1.30 +/- 0.65 (range, 0.61-2.94) respectively. The differences are not statistically significant. Boron uptake in malignant glioma was about three times higher than low grade glioma. We found a good correlation between boron uptake and time interval from BSH infusion, and 15-20 hours after BSH infusion the boron concentration in tumor was above 20 micrograms/g 10B in 69% of the malignant glioma patients; T/B ratio was above one in 75%, and above two in 44% of them. We recommend intra-venous infusion of BSH clinically since it is safer, and results in sufficient boron concentration in tumor, and the planned irradiation might be optimal around 15-20 hours after the BSH infusion for treating malignant glioma.

Topics: Adolescent; Adult; Aged; Borohydrides; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Child; Child, Preschool; Female; Glioma; Humans; Infant; Male; Middle Aged; Regression Analysis; Retrospective Studies; Sulfhydryl Compounds

The gene for epidermal growth factor receptor (EGFR) is amplified or overexpressed in high-grade gliomas but is low or undetectable in normal brain. Recently, there has been increasing interest in using epidermal growth factor (EGF)-based bioconjugates as targeting agents for brain tumors. In the present study, we have investigated the potential use of boronated EGF as a delivery agent for boron neutron capture therapy, which is based on the capture reaction that occurs when 10B, a stable isotope, is irradiated with low-energy thermal neutrons. A fourth generation starburst dendrimer was boronated and linked to EGF using heterobifunctional reagents. Either wild-type or EGFR gene transduced C6 glioma cells (C6EGFR), which expressed 10(5)-10(6) receptor sites/cell, were stereotactically implanted into the right cerebral hemisphere of Fischer rats. Four weeks later, the rats received either i.v. or intratumoral (i.t.) injection of 131I-labeled boronated starburst dendrimer (BSD) or BSD-EGF. The biodistribution of 131I-BSD-EGF and 131I-BSD was studied by means of whole-body scintigraphy, autoradiography, and gamma scintillation counting. Following i.t. injection of 131I-BSD-EGF, 21.8% of the injected dose per gram tissue (% ID/g) was localized in C6EGFR tumors at 24 h and 16.3% at 48 h compared to 5 and 1.3% ID/g in C6 wild-type tumors, respectively, and 0.01 and 0.006% ID/g, respectively, for i.v. injected animals at the corresponding times. In contrast, following i.t. injection of BSD-EGF, only 0.01-0.1% ID/g was localized in the liver and spleen at 24 and 48 h compared to 5-12% ID/g following i.v. injection. Our data indicate that direct i.t. injection can selectively deliver BSD-EGF to EGFR-positive gliomas and suggest that intracerebral administration may be the most effective way for delivering EGF-based bioconjugates to EGFR-positive brain tumors.

Topics: Animals; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Epidermal Growth Factor; ErbB Receptors; Glioma; Injections, Intralesional; Injections, Intravenous; Isotopes; Neoplasm Proteins; Rats; Tumor Cells, Cultured

Binding and toxicity of boronated phenanthridinium analogues were studied in vitro using cultured human malignant glioma cells. The compounds, 5-ortho- (5-o-CP), 5-para- (5-p-CP), 5-nido- (5-n-CP) and 6-nido-carboranyl phenanthridinium (6-n-CP) showed varying toxic effects. The cells were exposed to the compounds for 2 or 24 h. The span between non-toxic and toxic concentrations seemed to be very narrow. 5-p-CP was the most toxic compound, causing total cell death at a concentration of 5 micrograms/ml cell culture medium. None of the compounds showed toxic effects at a concentration of 1 microgram/ml. Viable cells incubated with the compounds at this concentration showed a > 100-fold accumulation of boron. Only approximately 1/4 of this accumulation was found in cells permeabilized and inactivated with acetone. Fluorescent images of acetone-treated cells showed clear uptake of the compounds in the cell nucleus, as for ethidium bromide, while for viable cells binding to structures other than DNA was also observed. These results were confirmed by subcellular boron determination. All tested compounds intercalate into DNA, as was demonstrated in cell-free systems with calf thymus DNA. The hypothesis is that the compounds are trapped in the cellular membranes of viable cells because of their lipophilicity, before reaching nuclear DNA.

Topics: Boron; Boron Compounds; Cell Nucleus; Cell-Free System; Cytoplasm; DNA, Neoplasm; Drug Screening Assays, Antitumor; Glioma; Humans; Phenanthridines; Tumor Cells, Cultured

Accumulation of boron in tumor tissue is an indispensable requirement for boron neutron capture therapy and it is important that the uptake is as high as possible. In this work we have studied the influence of electropermeabilization in vivo on the uptake of boron in normal and RG 2 glioma bearing Fischer 344 rats. Two different boron compounds, a sulfhydryl boron hydride (BSH) and a boronated porphyrin (BOPP), have been investigated. The rats were infused intravenously during 5 min with 175 micrograms BSH/g body weight or 12 micrograms BOPP/g body weight. Two electrodes were placed 5 mm apart in the brain and electropermeabilization was performed with eight square 400 V pulses at 4 and 7 min after the end of the infusion. After 6 h the animals were killed, and the boron content in the tumors and the surrounding brain was measured with neutron-activated autoradiography. In electropermeabilized healthy animals the BOPP uptake was low and limited to the electrode lesions, whereas BSH was spread extensively throughout the hemisphere. Rats with gliomas showed doubled (BOPP) to 10-fold (BSH) uptake of boron in the tumor when electropermeabilization was performed as compared with untreated animals. We conclude that electropermeabilization in the future may provide an interesting possibility to increase the uptake of certain boron compounds before neutron capture therapy.

Topics: Animals; Borohydrides; Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Membrane Permeability; Deuteroporphyrins; Disease Models, Animal; Electric Stimulation; Female; Glioma; Injections, Intravenous; Male; Neoplasm Transplantation; Rats; Rats, Inbred F344; Sulfhydryl Compounds

To study the biodistribution of p-Boronophenylalanine in patients undergoing surgery for intracranial tumors or metastatic melanoma.. D,L-p-Boronophenylalanine was administered as boronophenylalanine.fructose in an intravenous bolus 1-4 h before the operation. Blood samples were collected for 24 h from the time of administration of the compound, and the blood boron elimination parameters were determined. For the glioma patients tumor samples were obtained and skin, dura, periosteum, and surrounding brain samples were collected whenever possible. For the metastatic melanoma patients tumor, fat, skin, and muscle were collected. Determination of the boron content was performed using inductively coupled plasma-atomic emission spectrometry. Twelve melanoma patients and six glioma patients participated in the study. The melanoma patients included four cases of cutaneous metastatic melanoma, six cases of metastatic melanoma to the lymph nodes and two cases of cerebral metastasis.. The results for the metastatic melanoma patients are encouraging with an average tumor:blood boron concentration ratio and standard deviation of about 4.4 +/- 3.2 and a maximum value of 10 for the cerebral metastasis. The glioma patients involved high grade glioma for which the tumor:blood ratio was 2.2 +/- 1.2.. The tumor:blood ratios for melanoma fulfil requirements for epithermal boron neutron capture therapy for cerebral melanoma metastases, whereas those for high grade glioma do not.

Topics: Boron; Boron Compounds; Boron Neutron Capture Therapy; Brain Neoplasms; Glioma; Humans; Melanoma; Phenylalanine; Radiation-Sensitizing Agents

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.. 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.. 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.. BNCT enhancement of fast-neutron irradiation is feasible in an in vivo tumor system.

Topics: Animals; Boron; Boron Neutron Capture Therapy; Brain Neoplasms; Cell Survival; Fast Neutrons; Glioma; Male; Rats; Rats, Inbred F344; Tumor Stem Cell Assay

Boron Neutron Capture Therapy (BNCT) is an attractive concept for radiation treatment of malignant tumours. The patients receive a 10B-carrying compound with selective uptake in tumour cells, after which they are irradiated with epithermal neutrons. Theoretically, the tumour cells are killed by the high-LET particles produces in 10B(n, alpha)7Li reactions inside or close to the cell nucleus, while healthy brain cells with no boron uptake will be spared. In practice, a successful BNCT depends on the actual boron-distribution in the tissue, and consequently a new boron-compound aimed for BNCT must undergo detailed bio-distribution studies before clinical trials. In experimental work there is accordingly a great need for methods for quantitative bio-distribution measurements in tissue samples. In this paper we present an improved technique for neutron activated autoradiography providing quantitative boron images of freeze-sectioned tissue specimens from highly malignant rat brain gliomas. Particular attention has been paid to the correlation with the morphology of the specimens and to the altered self-absorption properties due to freeze-drying. A self-absorption correction factor for tumour tissue has been experimentally determined.

Topics: Absorption; Animals; Autoradiography; Boron; Brain Neoplasms; Calibration; Freeze Drying; Glioma; Image Enhancement; Isotopes; Logistic Models; Microtomy; Neutron Capture Therapy; Rats; Signal Processing, Computer-Assisted; Tissue Fixation

Topics: Animals; Borohydrides; Boron; Brain; Brain Neoplasms; Glioma; Humans; Isotopes; Lithium; Rats; Sulfhydryl Compounds; Tumor Cells, Cultured

The effectiveness of boron neutron capture therapy is predicted to be dependent not only on the amount of boron taken up by the target cells but also on the intracellular distribution of boron. Using the isotopic imaging technique ion microscopy, we have quantitatively determined uptake and intracellular distribution of Na2B12H11SH, a promising boron drug for boron neutron capture therapy, in four human cell lines: U87 glioblastoma cells, HeLa epithelioid carcinoma cells, GM 2408b mutant skin fibroblasts, and GM 3348b skin fibroblasts. The boron uptake of all four cell lines, after exposure to 100-500 micrograms/ml Na2B12H11SH, increased as the dosages were increased but showed a tendency toward saturation. Boron was more concentrated in the cytoplasm than in the nucleus but was not strongly localized within cells. There were no significant differences in boron uptake among the four cell lines. A retention experiment identified at least two different intracellular boron pools, and cells lost greater than 60% of intracellular boron within 1 h upon changing to Na2B12H11SH-free medium, indicating a largely low affinity binding.

Topics: Boranes; Borohydrides; Boron; Brain Neoplasms; Carcinoma, Squamous Cell; Cell Line, Transformed; Culture Techniques; Fibroblasts; Glioma; HeLa Cells; Humans; Intracellular Fluid; Mass Spectrometry; Microscopy; Neutron Capture Therapy; Subcellular Fractions; Sulfhydryl Compounds; Tumor Cells, Cultured

Toxicity of mercaptoundecahydro-closo-dodecaborate (MHB, Na2H(11)10B12SH) and accumulation of MHB-derived 10B were studied in E7 neuroblastoma, C6 glioma, HeLa cells and embryonic lung LEP 19 fibroblasts in culture in exponential and stationary phases of growth (2- and 7-day-old cultures, respectively). The pilot study of acute toxicity, performed on C6 glioma cells, showed good tolerance of the drug up to 1000 micrograms/ml (4.8 x 10(-3) M), when cell growth slowed and a small part of the population was lethally damaged (8.3%, 20-h incubation interval). The changes became more extensive and appeared sooner (toward 5 h) at 2000 micrograms MHB/ml (9.5 x 10(-3) M). None of the four cell lines used was found to be affected in gross morphology or growth by 200 micrograms MHB/ml within a 5-day culture interval. When exposed to this dose for 4 h, the amount of 10B accumulated in cell lines at the exponential growth phase ranged from 0.51 to 4.4 ng/micrograms protein; in the stationary cultures of the corresponding cell phenotype, the 10B values were 3 to 10 times lower (0.12-1.2 ng/micrograms protein). Irrespective of the growth phase, the values achieved in C6 glioma cells were several times higher than in the other cell lines. Furthermore, in the glioma cells, particularly in the exponential phase of growth, accumulation of 10B proceeded against the marked concentration gradient. The data provide a new indication for the use of MHB for boron neutron capture therapy of brain tumors.

Topics: Animals; Borohydrides; Boron; Brain Neoplasms; Glioma; Isotopes; Mice; Neutrons; Radiotherapy, High-Energy; Sulfhydryl Compounds; Tumor Cells, Cultured

Sulfhydryl boron hydride (BSH) (10B enriched) is presently used for boron neutron capture therapy of malignant gliomas. BSH must be close to the target cells to be effective in the inactivation of cell proliferation because of the short range of the reaction products (5-9 microns). Clinical experience indicates that BSH is taken up in gliomas but it is not known to which structures it binds at the cellular level. In vitro tests on monolayer cultured cells have indicated that BSH does not bind, or only shows very weak binding, to single isolated cells. It is possible that BSH accumulates in tumor regions due to the special conditions in poorly vascularized tumor tissue, such as low pO2, low extracellular pH, metabolic gradients, and degenerative changes. To test this we incubated three types of multicellular tumor spheroids with BSH for different times and analyzed both penetration and binding. The spatial distribution of 10B in sections of the spheroids was analyzed by neutron capture autoradiography. We found extensive accumulation of 10B in the central regions of both glioma and colon carcinoma spheroids. The accumulation closely followed the pattern of the degenerative changes which were characterized by massive necrosis in the central regions of the colon carcinoma spheroids and by a continuously increasing frequency of pyknotic nuclei as a function of depth in the glioma spheroids. The accumulation of 10B in the prostatic carcinoma spheroids was much lower. The penetration assay, based on freeze-drying and vapor fixation, showed that BSH penetrated easily since 10B equilibrated within 5-15 min in the studied spheroids. Thus, the low accumulation in the prostatic carcinoma spheroids was not due to penetration difficulties. The results of the present study on cellular spheroids and the results from previous studies on transplanted tumors support the observation that BSH penetrates easily into the degenerative tumor areas and that 10B, for some tumor types, might accumulate in these regions as a result of the BSH administration.

Topics: Autoradiography; Borohydrides; Boron; Brain Neoplasms; Carcinoma; Colonic Neoplasms; Glioma; Humans; Isotopes; Male; Prostatic Neoplasms; Sulfhydryl Compounds; Tumor Cells, Cultured

The following boron-containing nucleoside and glucose derivatives have been synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT): 2'-O-(o-carboran-1-ylmethyl)uridine (4a), 3'-O-(o-carboran-1-ylmethyl)uridine (4b), sodium 7-(uridin-2'-ylmethyl)dodecahydro-7,8-dicarba-++ +nido-undecaborate (5), 5'-O-(o-carboran-1-ylmethyl)uridine (9), and 3'-O-(o-carboran-1-ylmethyl)-D-glucose (13). In vitro cellular uptake studies were performed with F98 rat glioma cells. Following 16 h incubation, cellular boron concentrations were determined by direct current plasma atomic emission spectroscopy (DCP-AES). Boron concentrations ranged from 65 to 103 micrograms/g of cells for the neutral closo structures compared with 1.5 micrograms/g of cells for the charged nido species. Cellular uptake of sodium mercaptoundecahydro-closo-dodecaborate (BSH), the compound currently being used in Japan for the treatment of malignant brain tumors by BNCT, was 2 micrograms/g of cells.

Topics: Animals; Boron; Glioma; Glucose; Neutrons; Radiotherapy, High-Energy; Rats; Tumor Cells, Cultured; Uridine

This investigation attempts to determine whether increased survival time seen when the F98 glioma model is treated with boron neutron capture therapy (BNCT) is a result of inhibition of tumor growth caused by radiation-induced alterations in endothelial cells and normal tissue components. This indirect effect of radiation has been called the tumor bed effect. A series of tumor-bearing rats was studied, using a standardized investigational BNCT protocol consisting of 50 mg/kg of Na2B12H11SH injected intravenously 14 to 17 hours before neutron irradiation at 4 x 10(12) n/cm2. Ten rats, serving as controls, received no treatment either before or after tumor implantation. A second group of 10 rats was treated with BNCT 4 days before tumor implantation; these animals received no further treatment. The remaining group of 10 rats received no pretreatment but was treated with BNCT 10 days after implantation. Histological and ultrastructural analyses were performed in 2 animals from each group 17 days after implantation. Survival times of the untreated control animals (mean, 25.8 days) did not differ statistically from the survival times of the rats in the pretreated group (mean, 25.5 days). The rats treated with BNCT after implantation survived significantly longer (P less than 0.02; mean, 33.2 days) than the controls and the preirradiated animals. Tumor size indices calculated from measurements taken at the time of death were similar in all groups. These results indicate that, with this tumor model, BNCT does not cause a tumor bed effect in cerebral tissue. The therapeutic gains observed with BNCT result from direct effects on tumor cells or on the peritumoral neovascularity.

Topics: Animals; Borohydrides; Boron; Brain Neoplasms; Caudate Nucleus; Energy Transfer; Glioma; Isotopes; Male; Neoplasm Transplantation; Neutrons; Radioactivity; Rats; Rats, Inbred F344; Sulfhydryl Compounds

The efficacy of boron neutron capture therapy (BNCT) for the treatment of intracerebrally implanted rat gliosarcomas was tested. Preferential accumulation of 10B in tumors was achieved by continuous infusion of the sulfhydryl borane dimer, Na4(10)B24H22S2, at a rate of 45-50 micrograms of 10B per g of body weight per day from day 11 to day 14 after tumor initiation (day 0). This infusion schedule resulted in average blood 10B concentrations of 35 micrograms/ml in a group of 12 gliosarcoma-bearing rats and 45 micrograms/ml in a group of 10 similar gliosarcoma-bearing rats treated by BNCT. Estimated tumor 10B levels in these two groups were 26 and 34 micrograms/g, respectively. On day 14, boron-treated and non-boron-treated rats were exposed to 5.0 or 7.5 MW.min of radiation from the Brookhaven Medical Research Reactor that yielded thermal neutron fluences of approximately 2.0 x 10(12) or approximately 3.0 x 10(12) n/cm2, respectively, in the tumors. Untreated rats had a median postinitiation survival time of 21 days. Reactor radiation alone increased median postinitiation survival time to 26 (5.0 MW.min) or 28 (7.5 MW.min) days. The 12 rats that received 5 MW.min of BNCT had a median postinitiation survival time of 60 days. Two of these animals survived greater than 15 months. In the 7.5 MW.min group, the median survival time is not calculable since 6 of the 10 animals remain alive greater than 10 months after BNCT. The estimated radiation doses to tumors in the two BNCT groups were 14.2 and 25.6 Gy equivalents, respectively. Similar gliosarcoma-bearing rats treated with 15.0 or 22.5 Gy of 250-kilovolt peak x-rays had median survival times of only 26 or 31 days, respectively, after tumor initiation.

Topics: Animals; Boranes; Borohydrides; Boron; Brain Neoplasms; Glioma; Isotopes; Neutrons; Rats; Rats, Inbred F344; Sulfhydryl Compounds; Sulfides

The purpose of the present study was to utilize a well-established rat glioma to evaluate boron neutron capture therapy for the treatment of malignant brain tumors. Boron-10 (10B) is a stable isotope which, when irradiated with thermal neutrons, produces a capture reaction yielding high linear energy transfer particles (10B + 1nth----[11B]----4He(alpha) + 7Li + 2.79 MeV). The F98 tumor is an anaplastic glioma of CD Fischer rat origin with an aggressive biological behavior similar to that of human glioblastoma multiforme. F98 cells were implanted intracerebrally into the caudate nuclei of Fischer rats. Seven to 12 days later the boron-10-enriched polyhedral borane, Na2B12H11SH, was administered intravenously at a dose of 50 mg/kg body weight at varying time intervals ranging from 3 to 23.5 hours before neutron irradiation. Pharmacokinetic studies revealed blood 10B values ranging from 0.33 to 10.5 micrograms/ml depending upon the time after administration, a T1/2 of 6.2 hours, normal brain 10B concentrations of 0.5 microgram/g, and tumor values ranging from 1.1 to 12.8 micrograms/g. No therapeutic gain was seen if the capture agent was given at 3 or 6 hours before irradiation with 4 x 10(12) n/cm2 (10 MW-min; 429 cGy). A 13.5-hour preirradiation interval resulted in a mean survival of 37.8 days (P less than 0.01), compared to 30.5 days (P less than 0.03) for irradiated controls and 22.1 days for untreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Boron; Brain Neoplasms; Energy Transfer; Glioma; Isotopes; Neutrons; Radiotherapy; Rats; Rats, Inbred F344

Topics: Animals; Boron; Boron Compounds; Brain; Brain Neoplasms; Dogs; Glioma; Humans; Isotopes; Melanoma; Methods; Mice; Neutrons

A CD 344 rat glioma model currently used to investigate boron neutron capture therapy (BNCT) was used to demonstrate an increased survival rate after thermal neutron irradiation enhanced by administration of 10B-enriched polyhedral borane, Na2B12H11SH. To investigate the possible effects of BNCT on normal and tumor microvasculature, we subjected animals to sublethal neutron irradiation with and without intravenous injection of 50 mg/kg of enriched 10B and performed histological and ultrastructural analyses. In the rats that did not undergo tumor transplantation, minimal detectable morphological changes in the microvasculature of the central nervous system were observed after treatment, both in the immediate posttreatment phase and at 10 months. Light microscopy of cerebral cortex and caudate nucleus showed normal cytoarchitecture with no evidence of vessel occlusion, hyalinization, thickening, or reactive gliosis. Electron microscopy demonstrated that the junctional complexes of the endothelial cells, the basal lamina, and the perivascular glia were comparable in both treated and control animals. In those animals examined at 18 months, pathological membrane-bound clusters of electron-dense vesicles were seen in pericytes. In the rats implanted with gliomas, vascular proliferation with evidence of breakdown of the blood-brain barrier and vasogenic edema occurred. In the irradiated animals, we noted increased peritumoral edema 3 days after treatment. At seven days, both increased peritumoral edema and necrosis were noted in the rats treated with BNCT. These observations show that the normal microvasculature of the central nervous system tolerates BNCT at the treatment parameters used in our experimental model; the progressive edema and necrosis found in the peritumoral region after BNCT indicate a pathological endothelial response.

Topics: Animals; Boron; Brain Neoplasms; Cell Line; Disease Models, Animal; Glioma; Isotopes; Male; Rats; Rats, Inbred F344

Topics: Boron; Brain Neoplasms; Gamma Rays; Glioma; Humans; Neutrons; Radiotherapy; Radiotherapy Dosage

Topics: Animals; Borates; Boron; Cesium; Disulfides; Glioma; Liver; Magnetic Resonance Imaging; Male; Neutrons; Radiotherapy; Rats; Rats, Inbred F344

Topics: Boron; Brain Neoplasms; Czechoslovakia; Glioma; Humans; Isotopes; Neutrons; Nuclear Reactors; Radiotherapy

The present report provides an overview of the multidisciplinary research effort on BNCT that currently is in progress at The Ohio State University. Areas under investigation include the preparation of boron containing monoclonal antibodies, the synthesis of boron containing derivatives of promazines and phathalocyanines, the development of a rat model for the treatment of glioblastoma by means of BNCT, the design of an accelerator-based neutron irradiation facility, and 10B concentration measurements using alpha track autoradiographic methods. Progress in each of these areas is described and the direction of future research is indicated.

Topics: Animals; Antibodies, Monoclonal; Boron; Cell Line; Cell Survival; Glioma; Radiotherapy; Rats; Tumor Cells, Cultured

Boron-neutron capture therapy (BNCT) is theoretically a highly selective treatment of infiltrating tumours, in that the tumoricidal heavy particle radiation is limited to a sphere of 10 microns around a tumour cell which is loaded with non-radioactive boron-10 atoms. There were 73 gliomas among the 83 cases treated by boron-neutron capture therapy. For grade III-IV cerebral gliomas, 5 and 10 year survival rates were an unimpressive 19 and 10% respectively. This was the result of technical problems such as unsatisfactory reactors and inadequate craniotomies for the majority of the patients. If the analysis was limited to those whose tumours had been irradiated with more than 2.5 x 10(12) neutrons/cm2 (yielding more than 3,000 rem or more), the 5 and 10 year survival were almost 100 and 50%. The longest surviving glioblastoma (grade IV) patient has lived in a satisfactory manner for the past 15 years. For the cases who had been treated with borderline doses (lethal or sublethal), interpretation of the postoperative CTs was frequently intriguing. Several cases had to undergo re-opening and occasionally even another BNCT, only to find no viable tumour tissue. Death occurred in some, either due to discontinuation of supportive treatments by local physicians, or due to excessive therapies by the author directly involved in the patient's care, both of whom had erroneously believed in recurrence. At autopsy, residual tumour cells were recognized only in the areas where the above-mentioned neutron fluence had not been delivered at the time of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Astrocytoma; Boron; Brain Neoplasms; Glioma; Humans; Isotopes; Male; Neutrons; Postoperative Complications; Tomography, X-Ray Computed

Monte-Carlo computer codes have been used to estimate the distribution of doses to borated and unborated tissues in head-sized phantoms when exposed to beams of 2 keV and 24 keV neutrons. For the application of such beams to boron neutron capture therapy (BNCT) these calculations show the superiority of 2 keV neutrons over 24 keV neutrons and the importance of using large-area beams. A 24 keV neutron beam has been used to irradiate HeLa cell cultures in vitro, with and without the addition of 10B, at various depths within a narrow polyethylene phantom. Survival data obtained from these experiments have been used to estimate depth-damage profiles for normal (unboronated) and tumour (boronated) brain tissues when exposed to 24 keV neutrons. A good differential between damage to normal and tumorous tissue is obtained under suitable irradiation conditions. Although lower-energy neutrons are probably preferable, these results demonstrate the possibility of using beams of 24 keV neutrons for the BNCT of brain tumours.

Topics: Boron; Brain Neoplasms; Cell Survival; Glioma; Humans; Isotopes; Methods; Neutrons; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Computer-Assisted

The vasculature and capillary permeability of gliomas induced by ethylnitrosourea in Sprague-Dawley rats were studied with horseradish peroxidase and Evans blue dye. The distribution of the boron-10 compound, Na2(10)B12H11SH, which is now in clinical use for boron neutron capture therapy (BNCT) for brain tumors, was investigated quantitatively using neutron-induced alpha-autoradiography. The vasculature and the degree of capillary permeability varied widely, depending mainly on the size of the glioma, and were often heterogeneous even in the same tumor. The distribution of boron-10 also varied, correlating to capillary permeability. The boron-10 concentration and the tumor:blood concentration ratio in large and medium-sized gliomas were adequate for successful BNCT. This study suggests that the vasculature and capillary permeability of the target brain tumor exert an important influence on the therapeutic efficacy of BNCT.

Topics: Animals; Boron; Brain; Brain Neoplasms; Capillary Permeability; Ethylnitrosourea; Evans Blue; Glioma; Horseradish Peroxidase; Isotopes; Rats; Rats, Inbred Strains; Reference Values

Monoclonal antibodies produced by hybrids of lymphoid cells can be raised against cancer cells. These antibodies can be used to detect certain cancers, and some monoclonals bind with relative selectivity to glioma-associated antigens. Various laboratories are studying the radiolocalization of human glioma antigens in tumor cells transplanted into animals, and this imaging technique is also being tested in patients. Methods have been developed to promote passage of these antibodies across the blood-brain barrier, and thereby, to increase their uptake in tumors. Either alone or in conjunction with macrophages, cytotoxins, or radiosensitizers, these antibodies may offer a high degree of selective tumor destruction with relative sparing of normal brain.

Topics: Animals; Antibodies, Monoclonal; Blood-Brain Barrier; Boron; Brain Neoplasms; Glioma; Humans; Immunotherapy; Isotope Labeling; Mannitol; Mice

The possibility of achieving a therapeutically useful tissue boron distribution for boron neutron capture therapy (BNCT) of cerebral gliomas with boron loaded tumor-specific antibodies is discussed. Using a theoretical tumor-immunological model and RBE dose-depth calculations, the effects of various parameters, e.g. antibody-antigen association constant, antigen site density, number of boron atoms per antibody molecule, etc., on the advantage depth, a relative measure of the resulting radiation dose distributions, are determined. It is shown that with this model a maximum in the advantage depth as a function of the blood boron concentration occurs, the position of which is dependent on the value of the parameters used. Frequently this maximum corresponds to a blood boron-10 concentration range of between 0.1 to 0.5 microgram 10B/g blood. It is concluded that given the pharmacodynamic properties of potentially useful antibody preparations for this type of tumor therapy, advantage depths significantly greater than those obtainable with existing "blood-brain-barrier" compounds are not likely to be easily achieved.

Topics: Antibodies, Neoplasm; Boron; Brain Neoplasms; Glioma; Humans; Methods; Neutrons

The essential feature of tumour therapy rests upon host-tumour interaction. To achieve therapeutic effects, a prerequisite to immunotherapy is the reduction of tumour cells in the host's body. Such measures should not be immunosuppressive. Cytotoxic chemotherapy is not appropriate in this regard. Supraradical surgery and non-specific radiotherapy are not desirable for preservation of nervous function, if their immunosuppression is not as severe as cytotoxic substances. Boron-neutron capture therapy is a highly specific and least immunosuppressive means of reducing tumour cells of the central nervous system. A brief introductory review of basic research is presented. The interim clinical results are: (i) Treatment of recurrent glioblastoma: Survival extension obtained by neutron capture therapy is 21.9 +/- 7.2 mos in contrast to that obtained by conventional treatments of 6.7 +/- 0.6 mos (p less than 0.001), (Total survival 26.3 +/- 6.7 mos); and (ii) only three patients including two glioblastoma cases were treated with neutron by the same surgeon who, by performing the first tumour operation, had the advantage in topographic knowledge for determining the radiation field. They survived 4, 5, and 6 years in almost fully active conditions. The new Musashi Institute of Technology Reactor Thermal Neutron Therapy Facility and the increased domestic production of boron-10 isotope have enlarged the therapeutic capacity to two dozen patients a year.

Topics: Adolescent; Adult; Animals; Boron; Brain; Brain Neoplasms; Child; Dogs; Glioma; Humans; Immunotherapy; Isotopes; Male; Mice; Microvilli; Middle Aged; Neutrons

Topics: Adult; Alpha Particles; Animals; Astrocytoma; Autoradiography; Boron; Brain Neoplasms; Cats; Child; Cobalt Radioisotopes; Female; Frontal Lobe; Glioblastoma; Glioma; Humans; Male; Methods; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Middle Aged; Neutrons; Pons

Topics: Animals; Boron; Brain Neoplasms; Endoplasmic Reticulum; Ependymoma; Glioma; Mice; Microscopy, Electron; Neoplasm Transplantation; Neoplasms, Experimental; Neutrons; Radiation Effects

Topics: Amines; Boron; Brain; Brain Neoplasms; Chemical Phenomena; Chemistry; Glioma; Metabolism; Research

Topics: Borates; Boron; Brain Neoplasms; Glioma; Humans; Neutrons

Topics: Boron; Brain Neoplasms; Glioma; Humans; Neutrons; Radioisotopes

Topics: Boron; Brain; Brain Neoplasms; Glioma; Humans; Neutrons; Radioisotopes

Topics: Boron; Brain; Brain Neoplasms; Glioblastoma; Glioma; Humans; Neutron Capture Therapy; Neutrons