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PubMed2006

Pharmacokinetic study of BSH and BPA in simultaneous use for BNCT.

In order to improve the effectiveness of boron neutron capture therapy (BNCT) for malignant gliomas, we examined the optimization of the administration of boron compounds in brain tumor animal model. We analyzed the concentration of boron atoms in intracranial C6 glioma -bearing rats using inductively coupled plasma atomic emission spectrometry. Each tumor-bearing rat received one of two different amounts of sodium borocaptate (BSH) and/or 500 mg/kg of boronophenylalanine (BPA) via intraperitoneal injection. We compared the boron concentrations of the tumor, the contralateral normal brain and the blood in rats of 3 different treatment groups (BSH alone, BPA alone and a combination of both BSH and BPA). Our results show that the tumor boron concentration increased much more than 30 microg/g by the coadministration of both compounds. Additionally, the blood boron concentration remained below 30 microg/g and the boron concentration in the normal brain was low (mean 4.7+/-1.1 microg/g). Even in comparison with the administration of BPA alone, coadministration of BPA and BSH shows an improved tumor/normal brain ratio of boron concentrations.

Animals↗
PubMed2005

Combination of boron and gadolinium compounds for neutron capture therapy. An in vitro study.

In neutron capture therapy, the therapeutic effect of the boron compound is based on alpha particles produced by the B(n, alpha) reaction while with the gadolinium compound the main radiation effect is from gamma rays derived from the Gd(n, gamma) reaction. The uptake and distribution within the tumor may be different among these compounds. Thus, the combination of the boron and gadolinium compounds may be beneficial for enhancing the radiation dose to the tumor. Chinese hamster fibroblast V79 cells were used. For the neutron targeting compounds, 10B (BSH) at 0, 5, 10, and 15 ppm, and 157Gd (Gd-BOPTA) at 0, 800, 1600, 2400, 3200, and 4800 ppm, were combined. The neutron irradiation was performed with thermal neutrons for 30 min. (neutron flux: 0.84 x 10(8) n/cm2/s in free air). The combination of the boron and gadolinium compounds showed an additive effect when the gadolinium concentration was lower than 1600 ppm. This additive effect decreased as a function of gadolinium concentration at 2400 ppm and resulted in no additive effect at more than 3200 ppm of gadolinium. In conclusion, the combination of the boron and gadolinium compounds can enhance the therapeutic effect with an optimum concentration ratio. When the gadolinium concentration is too high, it may weaken the boron neutron capture reaction due to the high cross-section of gadolinium compound against neutrons.

Animals↗
PubMed1980

[Use of antagonistic metals to correct copper metabolism in patients with hepatocerebral dystrophy].

For correcting copper metabolism in patients with hepatocerebral dystrophy use was made of boron compounds, particularly, of borax. The administration of the latter resulted in an increase of copper excretion in patients with all forms of hepatocerebral dystrophy. An inversely proportional relationship between the content of boron and copper in the patients' urine was discovered, the fact, that points to their competition. It is recommended to use boron compounds for removing copper from the body if this metal is accumulated in pathological quantities.

Adult↗
PubMed2000

Molecular mechanics calculations of 10-vertex boron cage compounds.

The model proposed earlier for molecular mechanics calculations of 7- and 12-vertex boranes, carboranes, and metallocarboranes has been extended to the case of 10-vertex borane cage compounds. To use the MM3 program with the standard connectivity file, and to avoid program alterations, the 10-vertex cages of the molecules were presented as a superposition of four formally independent fragments. Interactions between the fragments were described with a Hill-like potential, with the parameters adjusted for valence interactions. Standard values for the bond lengths and bond angles in the 10-vertex boron cage have been found by statistical analysis of X-ray data on borane cage compounds stored in the Cambridge Structural Database. Several substituted neutral molecules and anions have been considered, and good agreement of the calculated and experimental data has been obtained. Using the approach developed, the unknown structure of the [mu-B20H16O(CH2)4O(CH2)2CH(CH3)2]3- ion has been calculated.

Journal Article↗
PubMed2001

The hamster cheek pouch as a model of oral cancer for boron neutron capture therapy studies: selective delivery of boron by boronophenylalanine.

Herein we propose and validate the hamster cheek pouch model of oral cancer for boron neutron capture therapy (BNCT) studies. This model serves to explore new applications of the technique, study the biology and radiobiology of BNCT, and assess the uptake of boron compounds and response of tumor, precancerous tissue, and clinically relevant normal tissues. These issues are central to evaluating and improving the therapeutic gain of BNCT. The success of BNCT is dependent on the absolute amount of boron in the tumor, and the tumor:blood and tumor:normal tissue boron concentration ratios. Within this context, biodistribution studies are pivotal. Tumors were induced in the hamsters with a carcinogenesis protocol that uses dimethyl-1,2-benzanthracene and mimics spontaneous tumor development in human oral mucosa. The animals were then used for biodistribution and pharmacokinetic studies of boronophenylalanine (BPA). Blood, tumor, precancerous pouch tissue surrounding tumor, normal pouch tissue, tongue, skin, cheek mucosa, palate mucosa, liver, and spleen, were sampled at 0-12 h after administration of 300 mg BPA/kg. The data reveal selective uptake of BPA by tumor tissue and, to a lesser degree, by precancerous tissue. Mean tumor boron concentration was 36.9 +/- 17.5 ppm at 3.5 h and the mean boron ratios were 2.4:1 for tumor:normal pouch tissue and 3.2:1 for tumor:blood. Higher doses of BPA (600 and 1200 mg BPA/kg) increased tumor uptake. Potentially therapeutic absolute boron concentrations, and tumor:normal tissue and tumor:blood ratios can be achieved in the hamster oral cancer model using BPA as the delivery agent.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

The rationale and requirements for the development of boron neutron capture therapy of brain tumors.

The dismal clinical results in the treatment of glioblastoma multiforme despite aggressive surgery, conventional radiotherapy, and chemotherapy, either alone or in combination has led to the development of alternative therapeutic modalities. Among these is boron neutron capture therapy (BNCT). This binary system is based upon two key requirements: (1) the development and use of neutron beams from nuclear reactors or other sources with the capability for delivering high fluxes of thermal neutrons at depths sufficient to reach all tumor foci, and (2) the development and synthesis of boron compounds that can penetrate the normal bloodbrain barrier, selectively target neoplastic cells, and persist therein for suitable periods of time prior to irradiation. The earlier clinical failures with BNCT related directly to the lack of tissue penetration by neutron beams and to boron compounds that showed little specificity for and low retention by tumor cells, while attaining high concentrations in blood. Progress has been made both in neutron beam and compound development, but it remains to be determined whether these are sufficient to improve therapeutic outcomes by BNCT in comparison with current therapeutic regimens for the treatment of malignant gliomas.

Boron Neutron Capture Therapy↗
PubMedDate not supplied

Tissue uptake of BSH in patients with glioblastoma in the EORTC 11961 phase I BNCT trial.

PURPOSE: The uptake of the boron compound Na2B12H10-SH (BSH) in tumor and normal tissues was investigated in the frame of the EORTC phase I trial 'Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility' (protocol 11961). METHODS AND MATERIALS: The boron concentration in blood, tumor, normal brain, dura, muscle, skin and bone was detected using inductively coupled plasma-atomic emission spectroscopy in 13 evaluable patients. In a first group of 10 patients 100 mg BSH/kg bodyweight (BW) were administered; a second group of 3 patients received 22.9 mg BSH/kg BW. The toxicity due to BSH was evaluated. RESULTS: The average boron concentration in the tumor was 19.9 +/- 9.1 ppm (1 standard deviation (SD)) in the high dose group and 9.8 +/- 3.3 ppm in the low dose group, the tumor/blood ratios were 0.6 +/- 0.2 and 0.9 +/- 0.2, respectively. The highest boron uptake has been detected in the dura, very low uptake was found in the bone, the cerebro-spinal fluid and especially in the brain (brain/blood ratio 0.2 +/- 0.02 and 0.4 +/- 0.2). No toxicity was detected except flush-like symptoms in 2 cases during a BSH infusion at a much higher speed than prescribed. CONCLUSION: BSH proved to be safe for clinical application at a dose of 100 mg BSH/kg infused and at a dose rate of 1 mg/kg/min. The study underlines the importance of a further investigation of BSH uptake in order to obtain enough data for significant statistical analysis. The boron concentration in blood seems to be a quite reliable parameter to predict the boron concentration in other tissues.

Aged↗
PubMed2002

Mutagenic effect of borocaptate sodium and boronophenylalanine in neutron capture therapy.

PURPOSE: To investigate the mutagenic effect in boron neutron capture therapy (BNCT), Chinese hamster ovary cells were incubated with 10 B-enriched borocaptate sodium (BSH) or para-boronophenylalanine (BPA) before exposure to thermal neutrons, and the occurrence of mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus was measured. METHODS AND MATERIALS: BSH or BPA was added to cells 20 h or 2 h before irradiation and removed before irradiation. Cells were irradiated with thermal neutrons. The biologic end point of cell survival was measured by colony formation assay. The mutagenicity was calculated from the mutation frequency at the HPRT locus. RESULTS: The mutagenicity of BSH and BPA was similar to that of 10B boric acid when the cells were irradiated with neutrons at an isosurvival dose after 2-h preincubation. Preincubation with BSH for 20 h, compared with preincubation for just 2 h, had no effect on either cytotoxicity or mutagenicity in BNCT. However, with BPA, 20-h preincubation, compared with 2-h preincubation, caused an increase in the cell killing effect, but a decrease in the mutagenic effect of the BNCT. CONCLUSION: After 20-h incubation, BPA was less mutagenic than BSH. The mutagenic study of electroporated BPA or BSH revealed a reduced mutagenicity. These results suggest that the retention of these boron compounds in the cells causes a more accurate assault on the cell and lessens the chance of misrepair after neutron irradiation.

Animals↗
PubMed2003

New approach for the detection of BSH and its metabolites using capillary electrophoresis and electrospray ionization mass spectrometry.

Boron neutron capture therapy is a promising binary treatment for cancer. It is based on the nuclear fission that occurs when non-radioactive 10B absorbs thermal neutrons. One of the two boron compounds currently used in clinical trials for this therapy is BSH. To ensure differentiated retention in the tumour versus normal tissue prior to treatment, routine analytical methods to determine pharmacokinetics must be available. For this purpose we have developed a new, easy and time saving approach, in which the separation of boron derivatives is performed by means of capillary electrophoresis (CE). The CE method allows analyses to be performed in short times (less than 18 min), sensitively (LOD 8 pg loaded on the capillary) quantitatively (LOQ 5 microg/ml) and with a high efficiency of separation. Moreover it is simpler than HPLC and more reproducible (intra- and inter-day values were +/-1% and +/-3%, respectively), and does not require a specific column of derivatization. Mass spectrometry analysis of boron derivatives in different samples was also performed to ensure correct attribution of the CE peaks.

Boron Compounds↗
PubMed1995

[Neutron capturing irradiation: principle, current results and perspectives].

Neutron capture irradiation aims to selectively destroy the tumoral cells with nuclear reactions produced inside themselves. Therefore, 10B is selectively carried into tumours, being linked to a molecular vehicle. The tissues are then irradiated with thermal neutrons, and the boron neutron capture leads to the formation of alpha and 7Li particles which produce high levels of radiolytic damage along their range of 10 microns. Boron neutron capture therapy (BNCT) uses a thermal/epithermal neutron beam for irradiation, while boron neutron capture potentiation uses the addition of the captures in a fast neutron irradiation. A first trial, conducted in 1951 to 1961 in the USA to test BNCT on patients suffering of glioblastoma, was a failure, essentially because 10B was located in the cerebral capillaries rather than in the tumoral cells. Today, with great improvement in the boronated compounds which show an uptake preferentially inside the cells; the quality of neutron beams; and the knowledge of the microdosimetry of the technique, this technique may be clinically used to increase the local control of radioresistant tumours, like the high grade gliomas, cutaneous or uveal melanoma, and perhaps soft tissue sarcomas.

Borohydrides↗
PubMed2006

Homogeneous boron targeting of heterogeneous tumors for boron neutron capture therapy (BNCT): chemical analyses in the hamster cheek pouch oral cancer model.

OBJECTIVE: BNCT is a tumour cell targeted radiation therapy. Uniform targeting of heterogeneous tumours with therapeutically effective boron carriers would contribute to a therapeutic effect on all tumour cell populations and avoid radioresistant fractions. This remains an unresolved challenge. The aim of the present study was to evaluate the degree of variation in boron content delivered by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and the combined administration of (BPA+GB-10) in different portions of tumour, precancerous tissue around tumour and normal pouch tissue in the hamster cheek pouch oral cancer model. MATERIALS AND METHODS: Samples of different areas of tumour, precancerous tissue and normal pouch tissue were taken from tumour-bearing hamsters, 3h post-administration of i.p. BPA (15.5mg B/kg b.w.), or i.v. GB-10 (50mg B/kg b.w.), or 3h and 1.5h post-administration respectively of i.v. GB-10 (34.5mg B/b.w.) and sequential i.p. injections of BPA (total dose 31mg B/kg b.w.) given jointly. Boron content was evaluated by inductively coupled plasma optical emission spectroscopy (ICP-OES). The degree of homogeneity in boron targeting was assessed in terms of the coefficient of variation (V: [S.D./mean]x100) of boron values. Statistical analysis of the results was performed by one-way ANOVA and the least significant difference test. RESULTS: GB-10 and GB-10 plus BPA achieved respectively a statistically significant 1.8- and 3.3-fold increase in targeting homogeneity over BPA. CONCLUSIONS: The combined boron compound administration protocol contributes to homogeneous targeting of heterogeneous tumours and would be expected to increase therapeutic efficacy of BNCT.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

Practical methods using boronic acid compounds for identification of class C beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli.

Detection of the resistance mediated by class C beta-lactamases remains a challenging issue, considering that transferable plasmid-mediated class C beta-lactamases are of worldwide concern. Methods for the identification of strains that produce extended-spectrum beta-lactamases (ESBLs) or metallo-beta-lactamases (MBLs) have been developed and applied for routine use in clinical microbiology laboratories, but no practical methods for identification of plasmid-mediated class C producers have been established to date. We therefore developed three simple methods for clinical microbiology laboratories that allow identification of plasmid-mediated class C beta-lactamase-producing bacteria using a boronic acid derivative, 3-aminophenylboronic acid (APB), one of the specific inhibitors of class C beta-lactamases. Detection by the disk potentiation test was based on the enlargement of the growth-inhibitory zone diameter (by greater than or equal to 5 mm) around a Kirby-Bauer disk containing a ceftazidime (CAZ) or a cefotaxime (CTX) disk in combination with APB. In a double-disk synergy test, the discernible expansion of the growth-inhibitory zone around the CAZ or the CTX disk toward a disk containing APB was indicative of class C beta-lactamase production. A greater than or equal to eightfold decrease in the MIC of CAZ or CTX in the presence of APB was the criterion for detection in the microdilution test. By using these methods, Escherichia coli and Klebsiella pneumoniae isolates producing plasmid-mediated class C beta-lactamases, ACT-1, CMY-2, CMY-9, FOX-5, LAT-1, and MOX-1, were successfully distinguished from those producing other classes of beta-lactamases, such as ESBLs and MBLs. These methods will provide useful information needed for targeted antimicrobial therapy and better infection control.

Anti-Bacterial Agents↗
PubMed2003

The early successful treatment of glioblastoma patients with modified boron neutron capture therapy. Report of two cases.

We very effectively treated two patients with recurrent glioblastoma with modified boron neutron capture therapy (BNCT). In this paper, we describe the effectiveness of this treatment, and discuss the ways in which we modified the treatment. A 61-year-old man had a first operation for a right temporal glioblastoma, followed by full-dose chemo-radiotherapy. One year after the operation a partial removal was performed for the recurrent tumor at the same site. Fifty days after the second surgery, the patient received BNCT. We used an epithermal neutron beam as the neutron source, and used both sodium borocapate and boronophenylalanine as boron compounds with the craniotomy. Forty-eight hours after the BNCT, the follow-up MRI was applied to estimate the early effect of this treatment, which showed a 70% reduction in the contrast enhanced lesion, compared with the pretreatment MRI. In addition, the lesion/normal brain ratio of thallium-SPECT had improved markedly. No serial sequelae appeared after this treatment, and the patient remains healthy 6 months after the treatment. A 29-year-old young lady had a right temporal brain tumor, which was partially resected and followed by stereotactic radiosurgery for the residual mass. Seven months after the radiosurgery, a second operation was performed, which revealed the glioblastoma as diagnosis. We applied BNCT uneventfully for this patient with epithermal beam and two kinds of boron compounds as described above. For the treatment of the patient irradiation was applied without craniotomy with marked reduction of tumor volume immediately after the treatment.

Adult↗
PubMed2005

Regioselective debenzylation of C-glycosyl compounds by boron trichloride.

Boron trichloride has been found to promote selective deprotection of 1,2- or 1,3-cis oriented secondary benzyl ethers of per-benzylated C-glycosyl derivatives. The reactivity towards BCl(3) follows the order: C-4>or=C-2>C-6>C-3 for C-glucopyranosyl derivatives and C-3>or=C-4>C-6>C-2 for C-galactopyranosyl derivatives. Preparatively useful selective debenzylation at secondary positions was possible after careful control of reaction conditions.

Benzyl Compounds↗
PubMed2000

Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine.

PURPOSE: Boronophenylalanine (BPA) and sodium borocaptate (Na(2)B(12)H(11)SH or BSH) have been used clinically for boron neutron capture therapy (BNCT) of high-grade gliomas. These drugs appear to concentrate in tumors by different mechanisms and may target different subpopulations of glioma cells. The purpose of the present study was to determine if the efficacy of BNCT could be further improved in F98-glioma-bearing rats by administering both boron compounds together and by improving their delivery by means of intracarotid (i.c.) injection with or without blood-brain barrier disruption (BBB-D). METHODS AND MATERIALS: For biodistribution studies, 10(5) F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Eleven to 13 days later animals were injected intravenously (i.v.) with BPA at doses of either 250 or 500 mg/kg body weight (b.w.) in combination with BSH at doses of either 30 or 60 mg/kg b.w. or i.c. with or without BBB-D, which was accomplished by i.c. infusion of a hyperosmotic (25%) solution of mannitol. For BNCT studies, 10(3) F98 glioma cells were implanted intracerebrally, and 14 days later animals were transported to the Brookhaven National Laboratory (BNL). They received BPA (250 mg/kg b.w.) in combination with BSH (30 mg/kg b.w. ) by i.v. or i.c. injection with or without BBB-D, and 2.5 hours later they were irradiated with a collimated beam of thermal neutrons at the BNL Medical Research Reactor. RESULTS: The mean tumor boron concentration +/- standard deviation (SD) at 2.5 hours after i. c. injection of BPA (250 mg/kg b.w.) and BSH (30 mg/kg b.w.) was 56. 3 +/- 37.8 microgram/g with BBB-D compared to 20.8 +/- 3.9 microgram/g without BBB-D and 11.2 +/- 1.8 microgram/g after i.v. injection. Doubling the dose of BPA and BSH produced a twofold increase in tumor boron concentrations, but also concomitant increases in normal brain and blood levels, which could have adverse effects. For this reason, the lower boron dose was selected for BNCT studies. The median survival time was 25 days for untreated control rats, 29 days for irradiated controls, 42 days for rats that received BPA and BSH i.v., 53 days following i.c. injection, and 72 days following i.c. injection + BBB-D with subsets of long-term survivors and/or cured animals in the latter two groups. No histopathologic evidence of residual tumor was seen in the brains of cured animals. CONCLUSIONS: The combination of BPA and BSH, administered i.c. with BBB-D, yielded a 25% cure rate for the heretofore incurable F98 rat glioma with minimal late radiation-induced brain damage. These results demonstrate that using a combination of boron agents and optimizing their delivery can dramatically improve the efficacy of BNCT in glioma-bearing rats.

Animals↗
PubMed2005

Dative sigma- and pi-bonding in boron-nitrogen compounds: molecular structures of (CH3)2NB(CH3)N(CH3)B(CH3)2 and [(CH3)2B]2NN(CH3)2 determined by gas electron diffraction and quantum chemical calculations.

The molecular structures of dimethylamino[(dimethylboryl)methylamino]methylborane, Me2NBMeNMeBMe2 (1) and 1,1-bis(dimethylboryl)-2,2-dimethylhydrazine, (Me2B)2NNMe2 (2) have been determined by gas electron diffraction (GED), density functional theory calculations at the B3PW91/6-311++G** level and ab initio calculations at the MP2/6-311++G** level. 1 adopts an open structure similar to that of the isoelectronic hydrocarbon molecule permethylbutadiene; the central B-N bond distance at 148.0/149.3(7) pm (MP2/GED) corresponds to a single covalent N--B bond distance, the two terminal distances, 140.9/140.5(4) pm and 141.8/141.3(4) pm, correspond to the distance between N and B atoms joined by a covalent sigma-bond and a dative pi-bond. A closed form where the establishment of a dative bond between the terminal N and B atoms has led to the formation of a four-membered ring also corresponds to a minimum on the potential energy surface, but the energy is calculated to be 14.3 kJ mol(-1) higher at the MP2 level. This structure is also incompatible with the GED data. 2 adopts a structure in which a dative sigma-bond between the dimethylamino N atom and one of the boron atoms has led to the formation of a three-membered N(2)B ring. The dative sigma-bond distance is 165.5/164.0(13) pm, the two other bond distances in the ring are N-B=150.6/148.9(9) pm corresponding to a covalent sigma-bond and N-N=145.1/145.4(3) pm. The terminal B--N distance 139.6/138.9(9) pm is consistent with a covalent sigma-bond augmented by a dative pi-bond. An open Y-shaped structure also corresponds to a minimum on the potential energy surface, but the energy is 18.7 kJ mol(-1) higher (MP2) and it is incompatible with the GED data.

Journal Article↗