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PubMed2006

Effects of bifemelane on the calcium level and ATP release of the human origin astrocyte clonal cell.

The effect of bifemelane hydrochloride (bifemelane) was examined on human origin astrocyte clonal cells (Kings-1). Bifemelane (125 - 1,000 microM) induced a dose-dependent increase in the intracellular calcium concentration ([Ca(2+)](i)). In the highest concentration (1,000 microM), the drug caused the second large increase in [Ca(2+)](i) during the washing. The increase that occurred during the administration partially remained in the Ca(2+)-free medium and was blocked by 2-aminoethoxydiphenyl borate (2-APB), an IP(3)-receptor blocker, indicating that the source of Ca(2+) for the increase could be ascribed to the intracellular store. The increase in [Ca(2+)](i) was not observed during washing with Ca(2+)-free medium, but was observed when the washing was performed with Ca(2+)-containing medium. Bifemelane caused a dose-dependent ATP release, but histamine and carbachol, which induced a large increase in [Ca(2+)](i), had no effects on the ATP release. The effects on the [Ca(2+)](i) were blocked by pretreatment with pyridoxal phosphate-6-azophenyl-2',4' disulfonic acid, a P2-receptor antagonist. Although the mechanisms of ATP release induced by the drug have not been elucidated yet, the present results demonstrate that the increase in [Ca(2+)](i) induced by bifemelane is not due to its direct effect on the cells, but is dependent upon the ATP released from the cells.

Adenosine Triphosphate↗
PubMed1998

Selective delivery of 10B to soft tissue sarcoma using 10B-L-borophenylalanine for boron neutron capture therapy.

Boron neutron capture therapy (BNCT) may improve the locoregional control of radio/chemoresistant tumours like soft tissues sarcomas (STS). This technique uses the 10B(n,alpha)7Li nuclear reaction to destroy tumour cells, provided that a sufficient amount of 10B may be carried selectively into them. In order to evaluate the targeting potential of 10B-L-borophenylalanine (BPA) a 10B biodistribution study was carried out in 24 Wistar rats bearing Yoshida sarcoma. Six animals received increasing intraperitoneal doses of BPA (300, 600 and 1200 mg kg-1), while the remainder received a BPA dose of 600 mg kg-1 but with a sacrifice at six different time points: 1, 2, 4, 6, 9 and 12 h. The 10B concentrations in the tumours, normal tissues and blood were analysed with neutron capture radiography (NCR). The analysis shows that 36 micrograms g-1 (+/- 4 SD) of 10B may be incorporated into the tumour, with a ratio of 13 (+/- 4 SD) versus the muscle and a ratio of 15 (+/- 3 SD) versus the blood, 6 h after an intraperitoneal injection of 600 mg kg-1 of BPA. The BPA appears to be abundantly incorporated in the tumour, and the kidney proximal tubule area. These data suggest that BNCT using BPA may provide an improved therapeutic ratio for the treatment of STS.

Animals↗
PubMed2001

Advances in osmotic opening of the blood-brain barrier to enhance CNS chemotherapy.

The blood-brain barrier (BBB) to water-soluble drugs and macromolecules can be opened in vivo by infusing a hypertonic solution of arabinose or mannitol into the carotid artery for 30 sec. Opening involves widening of tight junctions between endothelial cells of the cerebrovasculature and is mediated by endothelial cell shrinkage, vascular dilatation associated with removal of water from brain, and modulation of the contractile state of the endothelial cytoskeleton and junctional proteins by increased intracellular calcium. A 10-fold increase in BBB permeability to intravascular substances, lasting about 10 min following osmotic exposure, reflects both increased diffusion and bulk fluid flow from blood into brain. Furthermore, recent evidence indicates that the duration of peak BBB opening can be extended beyond 30 min, by pre-treatment with a Na(+)/Ca(2+) channel blocker. In experimental animals, the osmotic method has been used to grant wide access to brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, viral vectors for gene therapy and enzymes. Ongoing multi-centre clinical studies suggest that the method, when used with intra-arterially administered anticancer drugs, can prolong survival in patients with malignant brain tumours, with minimal morbidity. However, controlled clinical trials are critical to see if the osmotic procedure with intra-arterial drugs enhances survival in brain tumour patients compared with intra-arterial drug alone.

Antineoplastic Agents↗
PubMed2001

A pharmacokinetic model for the concentration of 10B in blood after boronophenylalanine-fructose administration in humans.

An open two-compartment model has been developed for predicting (10)B concentrations in blood after intravenous infusion of the l-p-boronophenylalanine-fructose complex (BPA-F) in humans and derived from studies of pharmacokinetics in 24 patients in the Harvard-MIT Phase I clinical trials of BNCT. The (10)B concentration profile in blood exhibits a characteristic rise during the infusion to a peak of approximately 32 microg/g (for infusion of 350 mg/kg over 90 min) followed by a biphasic exponential clearance profile with half-lives of 0.34 +/- 0.12 and 9.0 +/- 2.7 h, due to redistribution and primarily renal elimination, respectively. The model rate constants k(1), k(2) and k(3) are 0.0227 +/- 0.0064, 0.0099 +/- 0.0027 and 0.0052 +/- 0.0016 min(-1), respectively, and the central compartment volume of distribution, V(1), is 0.235 +/- 0.042 kg/kg. The validity of this model was demonstrated by successfully predicting the average pharmacokinetic response for a cohort of patients who were administered BPA-F using an infusion schedule different from those used to derive the parameters of the model. Furthermore, the mean parameters of the model do not differ for cohorts of patients infused using different schedules.

Adult↗
PubMed2001

Boronated dipeptide borotrimethylglycylphenylalanine as a potential boron carrier in boron neutron capture therapy for malignant brain tumors.

Takagaki, M., Ono, K., Masunaga, S-I., Kinashi, Y., Oda, Y., Miyatake, S-I., Hashimoto, N., Powell, W., Sood, A. and Spielvogel, B. F. Boronated Dipeptide Borotrimethylglycylphenylalanine as a Potential Boron Carrier in Boron Neutron Capture Therapy for Malignant Brain Tumors. Radiat. Res. 156, 118-122 (2001).A boronated dipeptide, borotrimethylglycylphenylalanine (BGPA), was synthesized as a possible boron carrier for boron neutron capture therapy (BNCT) for malignant brain tumors. In vitro, at equal concentrations of (10)B in the extracellular medium, BGPA had the same effect in BNCT as p-boronophenylalanine (BPA). Boron analysis was carried out using prompt gamma-ray spectrometry and track-etch autoradiography. The tumor:blood and tumor:normal brain (10)B concentration ratios were 8.9 +/- 2.1 and 3.0 +/- 1.2, respectively, in rats bearing intracranial C6 gliosarcomas using alpha-particle track autoradiography. The IC(50), i.e. the dose capable of inhibiting the growth of C6 gliosarcoma cells by 50% after 3 days of incubation, was 5.9 x 10(-3) M BGPA, which is similar to that of 6.4 x 10(-3) M for BPA. The amide bond of BGPA is free from enzymatic attack, since it is protected from hydrolysis by the presence of a boron atom at the alpha-carbon position of glycine. These results suggest promise for the use of this agent for BNCT of malignant brain tumors. Further preclinical studies of BGPA are warranted, since BGPA has advantages over both BPA and BSH.

Alanine↗
PubMed2003

Inborn errors in metabolism and 4-boronophenylalanine-fructose-based boron neutron capture therapy.

Infusions of boronophenylalanine-fructose complex (BPA-F), at doses up to 900 mg/kg of BPA and 860 mg/kg of fructose, have been used to deliver boron to cancer tissue for boron neutron capture therapy (BNCT). In patients with phenylketonuria (PKU), phenylalanine accumulates, which is harmful in the long run. PKU has been an exclusion criterion for BPA-F-mediated BNCT. Fructose is harmful to individuals with hereditary fructose intolerance (HFI) in amounts currently used in BNCT. The harmful effects are mediated through induction of hypoglycemia and acidosis, which may lead to irreversible organ damage or even death. Consequently, HFI should be added as an exclusion criterion for BNCT if fructose-containing solutions are used in boron carriers. Non-HFI subjects may also develop symptoms, such as gastrointestinal pain, if the fructose infusion rate is high. We therefore recommend monitoring of glucose levels and correcting possible hypoglycemia promptly. Except for some populations with extremely low PKU prevalence, HFI and PKU prevalences are similar, approximately 1 or 2 per 20,000.

Abdominal Pain↗
PubMed1988

Measurement of inositol in uremic serum by selected ion monitoring.

A highly sensitive and specific quantitative assay for inositol in serum has been developed. Uremic serum, to which hexahydroxybenzene as an internal standard was added, was deproteined with trichloroacetate. The supernatant aqueous phase was taken after lipids in serum were removed with chloroform, and was lyophilized. The dried powder was converted to butylboronate derivatives by reaction with 5% n-butylboronate (pyridine solution). The reaction mixture was gas chromatographed on fused silica megabore column DB-1, and assayed by electron impact mass spectrometry using selected ion monitoring. Inositol was quantified by the internal standard method. It was possible to determine concentrations as low as 0.1 microgram/ml in 0.5 ml of serum sample with a relative standard deviation of less than 5%. The serum inositol concentration from fifteen fasting patients with chronic renal failure was 39.1 +/- 18.2 micrograms/ml, significantly higher than that of control subjects (5.1 +/- 2.1 micrograms/ml). In the fifteen fasting patients, serum inositol was linearly related to blood urea nitrogen (r = 0.96).

Adult↗
PubMed2006

Characterization and inhibition of SARS-coronavirus main protease.

Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel human coronavirus (CoV). During the 2003 epidemic, the disease rapidly spread from its origin in southern China to other countries and affected almost 8000 patients, which resulted in about 800 fatalities. A chymotrypsin-like cysteine protease named 3C-like protease (3CLpro) is essential for the life cycle of the SARS-CoV. This main protease is responsible for maturation of functional proteins and represents a key anti-viral target. HPLC and fluorescence-based assays have been used to characterize the protease and to determine the potency of the inhibitors. The fluorogenic method monitoring the increase of fluorescence from the cleavage of a peptide substrate containing an Edans-Dabcyl fluorescence quenching pair at two ends has enabled the use of high throughput screening to speed up the drug discovery process. Several groups of inhibitors have been identified through high throughput screening and rational drug design approaches. Thus, alpha,beta-unsaturated peptidomimetics, anilides, metal-conjugated compounds, boronic acids, quinolinecarboxylate derivatives, thiophenecarboxylates, phthalhydrazide-substituted ketoglutamine analogues, isatin and natural products have been identified as potent inhibitors of the SARS-CoV main protease. The different classes of inhibitors reported in these studies are summarized in this review. Some of these inhibitors could be developed into potential drug candidates, which may provide a solution to combat possible reoccurrence of the SARS and other life-threatening viruses with 3CL proteases.

Amino Acid Sequence↗
PubMed2006

The synthesis and use of boronated amino acids for boron neutron capture therapy.

The treatment of cancer remains one of the most challenging problems for humanity. Boron neutron capture therapy (BNCT) is a binary approach for cancer treatment that is particularly attractive in treating high-grade gliomas and metastatic brain tumors. Among types of boron-containing molecules used as BNCT agents, boronated amino acids have received significant attention for their preferentially uptake by growing tumor cells. This review emphasizes the synthesis of boronated amino acids.

Amino Acids↗
PubMed2006

Boron containing macromolecules and nanovehicles as delivery agents for neutron capture therapy.

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10 is irradiated with low energy thermal neutrons to yield high linear energy transfer (LET) alpha particles ((4)He) and recoiling lithium -7((7)Li) nuclei. For BNCT to be successful, a sufficient number of (10)B atoms ( approximately 10(9) atoms/cell) must be selectively delivered to the tumor and enough thermal neutrons must be absorbed by them to sustain a lethal (10)B(n, alpha) (7)Li capture reaction. BNCT primarily has been used to treat patients with brain tumors, and more recently those with head and neck cancer. Two low molecular weight (LMW) boron delivery agents currently are being used clinically, sodium borocaptate and boronophenylalanine. However, a variety of high molecular weight (HMW) agents consisting of macromolecules and nanovehicles have been developed. This review will focus on the latter which include: monoclonal antibodies, dendrimers, liposomes, dextrans, polylysine, avidin, folic acid, and epidermal and vascular endothelial growth factors (EGF and VEGF). Procedures for introducing boron atoms into these HMW agents and their chemical properties will be discussed. In vivo studies on their biodistribution will be described, and the efficacy of a subset of them, which have been used for BNCT of tumors in experimental animals, will be discussed. Since brain tumors currently are the primary candidates for treatment by BNCT, delivery of these HMW agents across the blood-brain barrier presents a special challenge. Various routes of administration will be discussed including receptor-facilitated transcytosis following intravenous administration, direct intratumoral injection and convection enhanced delivery by which a pump is used to apply a pressure gradient to establish bulk flow of the HMW agent during interstitial infusion. Finally, we will conclude with a discussion relating to issues that must be addressed if these HMW agents are to be used clinically.

Animals↗
PubMed1995

Prompt gamma ray spectrometry for in vivo measurement of boron-10 concentration in rabbit brain tissue.

Boron-10 concentrations in the brain of live rabbits were measured by prompt gamma ray spectrometry at intervals over a 24-hour period. Boron-10 concentrations in the blood and cerebrospinal fluid (CSF) were also measured. Animals were killed at each interval to obtain brain tissues to measure the boron-10 concentration in the brainstem, cerebral cortex, cerebellar cortex, and basal ganglia, as well as the whole brain. Boron-10 concentrations in the live brain did not differ significantly from those measured in whole brain tissue. Boron-10 concentrations in the blood were much higher than in the brain at each interval after injection. These boron-10 concentrations showed a similar pattern of initial rapid decrease, followed by a more gradual decrease. There was little boron-10 present in the CSF. The brainstem contained a significantly larger concentration of boron-10 than the other tissues. Prompt gamma ray spectrometry has the potential for direct measurement of boron-10 concentrations in the brain of patients undergoing boron neutron capture therapy.

Animals↗
PubMedDate not supplied

Liposomes containing boronophenylalanine for boron neutron capture therapy.

In the present work, liposomes loaded with Boronophenylalanine (BPA), with or without stabilization, were formulated for the application in boron neutron capture therapy. BPA was encapsulated into liposomes as a complex with fructose, but also as a free drug in two different pH buffers. The influence of critical variables (cholesterol content, drug:lipid molar ratio, osmotic stress of liposomes containing hyperosmotic drug solution) on liposome morphology and drug content was evaluated. The drug content and dissolution profile of different BPA loaded liposomes were also studied. The physical stability of liposomes in terms of changes in the size distribution in different osmotic pressure buffers and the chemical oxidation of phospholipids during storing conditions were investigated. The encapsulation efficiencies of all formulations were always satisfactory, being between 20-48%; even when the liposomes were exposed to high osmotic stress, the particle size was below 200 nm. The BPA-fructose complex loaded liposomes showed a slower drug release profile.

Boron Compounds↗
PubMed2000

Treatment of isografted 9L rat brain tumors with beta-5-o-carboranyl-2'-deoxyuridine neutron capture therapy.

beta-5-o-Carboranyl-2'-deoxyuridine (D-CDU) is a nontoxic pyrimidine nucleoside analogue designed for boron neutron capture therapy of brain tumors. In vitro studies indicated that D-CDU accumulates to levels 92- and 117-fold higher than the extracellular concentration in rat 9L and human U-251 glioma cells, respectively, and persists for several hours at levels 5-fold higher than the extracellular concentration. Furthermore, D-CDU was not toxic to rats injected i.p. with up to 150 mg/kg. On the basis of these studies, D-CDU was evaluated as a neutron capture therapy agent using rats bearing stereotactically implanted intracranial 9L tumors at single i.p. doses of 30 mg/kg and 150 mg/kg of D-CDU (20% 10B enriched), given 2 h before irradiation with thermal neutrons. Boron concentrations in tumors 2 h after dosing were 2.3 +/- 1.6 and 7.4 +/- 1.3 micrograms boron/g tissue (mean +/- SD), corresponding to tumor/brain ratios of 11.5 +/- 3.6 and 6.8 +/- 2.0 micrograms boron/g tissue for the low and high doses, respectively. All untreated animals died within 28 days, whereas half survived at days 32, 55, and 38 for groups receiving neutrons only, 30 mg/kg D-CDU, and 150 mg/kg D-CDU, respectively. Odds ratios of all treatment groups differed significantly from the untreated group (P < 0.002; logrank test). The median survival time for the 30 mg/kg-treated group but not for the 150 mg/kg-treated group was significantly longer than for rats treated with neutrons only (P = 0.036), which may correlate with the decreased tumor selectivity for D-CDU observed at the higher dose. Additional pharmacodynamic studies are warranted to determine optimal dosing strategies for D-CDU.

Animals↗
PubMed2001

Atomic emission method for total boron in blood during neutron-capture therapy.

BACKGROUND: Boron neutron-capture therapy (BNCT) is a drug-targeted binary radiotherapy for cancer. The (10)B capture of thermal neutrons induces secondary radiation within cells during irradiation. The most widely used boron carrier is 4-dihydroxyborylphenylalanine (BPA). The duration and timing of the irradiation is adjusted by monitoring (10)B concentrations in whole blood. METHODS: We developed a new method for boron determination that uses inductively coupled plasma atomic emission spectrometry (ICP-AES) and protein removal with trichloroacetic acid before analysis. This method was compared with the established but tedious inductively coupled plasma mass spectrometry (ICP-MS), which uses wet ashing as sample pretreatment. Erythrocyte boron concentrations were determined indirectly on the basis of plasma and whole blood boron concentrations and the hematocrit. The hematocrit was determined indirectly by measuring calcium concentrations in plasma and whole blood. RESULTS: Within- and between-day CVs were <5%. The recoveries for boron in whole blood were 95.6-96.2%. A strong correlation was found between results of the ICP-AES and ICP-MS (r = 0.994). Marked differences in plasma and erythrocyte boron concentrations were observed during and after infusion of BPA fructose complex. CONCLUSIONS: The present method is feasible, accurate, and one of the fastest for boron determination during BNCT. Our results indicate that it is preferable to determine boron in plasma and in whole blood. Indirect erythrocyte-boron determination thus becomes possible and avoids the impact of preanalytical confounding factors, such as the influence of the hematocrit of the patient. Such an approach enables a more reliable estimation of the irradiation dose.

Adult↗
PubMed2001

Quantitative imaging and microlocalization of boron-10 in brain tumors and infiltrating tumor cells by SIMS ion microscopy: relevance to neutron capture therapy.

Boron neutron capture therapy (BNCT) is dependent on the selective accumulation of boron-10 in tumor cells relative to the contiguous normal cells. Ion microscopy was used to evaluate the microdistribution of boron-10 from p-boronophenylalanine (BPA) in the 9L rat gliosarcoma and the F98 rat glioma brain tumor models. Four routes of BPA administration were used: i.p. injection, intracarotid (i.c.) injection [with and without blood-brain barrier disruption (BBB-D)], and continuous timed i.v. infusions. i.p. injection of BPA in the 9L gliosarcoma resulted in a tumor-to-brain (T:Br) boron-10 concentration ratio of 3.7:1 when measured at the tumor-normal brain interface. In the F98 glioma, i.c injection of BPA resulted in a T:Br ratio of 2.9:1, and this increased to 5.4:1 when BBB-D was performed. The increased tumor boron uptake would potentially enhance the therapeutic ratio of BNCT by >25%. At present, ion microscopy is the only technique to provide a direct measurement of the T:Br boron-10 concentration ratio for tumor cells infiltrating normal brain. In the 9L gliosarcoma, this ratio was 2.9:1 after i.p. administration. In the F98 glioma, i.c injection resulted in a ratio of 2.2:1, and this increased to 3.0:1 after BBB-D. Ion microscopy revealed a consistent pattern of boron-10 microdistribution for both rat brain tumor models. The boron-10 concentration in the main tumor mass (MTM) was approximately twice that of the infiltrating tumor cells. One hour after a 2-h i.v. infusion of BPA in rats with the 9L gliosarcoma, tumor boron-10 concentrations were 2.7 times higher than that of infiltrating tumor cells [83 +/- 23 microg/g tissue versus 31 +/- 12 microg/g tissue (mean +/- SD)]. Continuous 3- and 6-h i.v. infusions of BPA in the 9L gliosarcoma resulted in similar high boron-10 concentrations in the MTM. The boron-10 concentration in infiltrating tumor cells was two times lower than the MTM after a 3-h infusion. After 6 h, the boron-10 concentration in infiltrating tumor cells had increased nearly 90% relative to the 2- and 3-h infusions. A 24-h i.v. infusion resulted in similar boron-10 levels between the MTM and the infiltrating tumor cells. Boron concentrations in the normal brain were similar for all four infusion times (approximately 20 microg/g tissue). These results are important for BNCT, because clinical protocols using a 2-h infusion have been performed with the assumption that infiltrating tumor cells contain equivalent amounts of boron-10 as the MTM. The results reported here suggest that this is not the case and that a 6-h or longer infusion of BPA may be necessary to raise boron-10 levels in infiltrating tumor cells to that in the MTM.

Animals↗
PubMed2001

Boron neutron capture therapy for the treatment of oral cancer in the hamster cheek pouch model.

We have proposed and validated the hamster cheek pouch model of oral cancer for boron neutron capture therapy (BNCT) studies and shown that boronophenylalanine delivers potentially therapeutic 36.9 +/- 17.5 ppm boron to tumor tissue with tumor:normal tissue and tumor:blood ratios of 2.4:1 and 3.2:1, respectively. Here we report the first evidence of the usefulness of BNCT for the treatment of oral cancer in an experimental model. We assessed the response of hamster cheek pouch tumors, precancerous tissue, and normal oral tissue to boronophenylalanine-mediated BNCT using the thermalized epithermal beam of the RA-6 Reactor at the Bariloche Atomic Center. BNCT leads to complete remission by 15 days posttreatment in 78% of tumors and partial remission in an additional 13% of tumors with virtually no damage to normal tissue.

9,10-Dimethyl-1,2-benzanthracene↗