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PubMed1991

The separation of chondroitin sulfate disaccharides and hyaluronan oligosaccharides by capillary zone electrophoresis.

We have developed techniques for the separation of unsulfated (2-acetamido-2-deoxy-3-O-(4-deoxy-alpha-L-threo- hex-4-enopyranosyluronicacid)-D-galactose and -D-glucose), monosulfated (2-acetamido-2-deoxy-3- O-(4-deoxy-2-O-sulfo-alpha-L-threo-hex-4-enopyranosyluronic acid)-D-galactose and 2-acetamido-2-deoxy-3-O-(4-deoxy-alpha-L-threo-hex- 4-enopyranosyluronic acid)-4-sulfo-D-galactose and -6-sulfo-D-galactose),disulfated (2-acetamido-2-deoxy-3-O-(4-deoxy-2-O-sulfo-alpha-L-threo-hex-4- enopyranosyluronic acid)-4-sulfo-D-galactose and -6-sulfo-D-galactose and 2-acet-amido-2-deoxy-3-O-(4-deoxy-alpha-L-threo-hex-4-enopy- ranosyluronic acid)-4,6-di-O-sulfo-D-galactose), and trisulfated (2-acetamido-2-deoxy-3-O-(4-deoxy-2-O- sulfo-alpha-L-threo-hex-4-enopyranosyluronic acid)-4,6-di-O-sulfo-D-galactose) isomers of chondroitin using capillary zone electrophoresis. In addition, it is possible to separate oligomers of hyaluronan by similar protocols. These techniques represent a rapid, sensitive, and reproducible technique for the assay of these molecules from digests of connective tissues.

Boric Acids↗
PubMed1985

A transition-state-analog inhibitor influences zinc-binding by Aeromonas aminopeptidase.

The transition-state-analog inhibitor, 1-butaneboronic acid, markedly enhances the uptake of one g-atom of Zn2+ ions from a metal ion buffer system by Zn-depleted Aeromonas aminopeptidase. In contrast, a substrate-analog inhibitor, n-valeramide, does not perturb the equilibrium between Zn2+ ions and the enzyme in a metal ion buffer system. These results establish a role for metal ions in the binding of 1-butaneboronic acid to Aeromonas amino-peptidase and strongly imply that a bound Zn2+ ion interacts directly with substrate during catalysis but not during initial binding of substrate.

Aeromonas↗
PubMed1986

Phenyl-n-butylborinic acid is a potent transition state analog inhibitor of lipolytic enzymes.

The cholesterol esterase and lipoprotein lipase catalyzed hydrolyses of the water-soluble substrate p-nitrophenyl butyrate are competitively inhibited by butaneboronic acid and phenylboronic acid. Phenyl-n-butylborinic acid has been synthesized and characterized as an ultrapotent transition state analog inhibitor: Ki = 2.9 +/- 0.6 nM and 1.7 +/- 0.3 microM for the cholesterol esterase and lipoprotein lipase reactions, respectively. These results are interpreted in terms of transition state structure and stabilization.

Animals↗
PubMed1994

Neutron capture therapy of the 9L rat gliosarcoma using the p-boronophenylalanine-fructose complex.

PURPOSE: Intraperitoneal (IP) injection of the solubilized fructose complex of L-p-boronophenylalanine (BPA-F) produced higher boron concentrations in a rat brain tumor model than was possible using intragastric (IG) administration of L-p-boronophenylalanine (BPA). The effectiveness of IP BPA-F was compared to IG BPA in boron neutron capture therapy irradiations of the 9L rat brain tumor model. METHODS AND MATERIALS: The time course of boron accumulation in tumor and normal tissues was determined in male F344 rats bearing either SC or intracerebral 9L gliosarcomas following a single IP injection of BPA-F. On day 14 after inoculation of intracranial tumors, rats were irradiated with single doses of either: 250 kVp X rays; the thermal neutron beam of the Brookhaven Medical Research Reactor following IG administration of BPA; or thermal neutrons following IP injection of BPA-F. Magnetic resonance imaging was used to visualize the tumor scars and to assess damage to the normal brain in long-term survivors. RESULTS: 4 h after IP injection of 1200 mg/kg of BPA-F the boron concentrations in tumor, blood, and normal brain were 89.6 +/- 7.6, 27.7 +/- 2.8 and 17.5 +/- 1.5 micrograms 10B/g, respectively. Two IG doses of BPA (750 mg/kg each, 3 h apart) produced 39 +/- 5, 12 +/- 1 and 10 +/- 1 micrograms 10B/g in tumor, blood and brain, respectively at 5 h after the second dose. Three groups of rats were treated with thermal neutrons: one following IG BPA and two groups following IP BPA-F. The total physical absorbed doses to the tumor in the three BNCT groups were 15.5 Gy (IG BPA, n = 12), 17.0 Gy (IP BPA-F, n = 8), and 31.5 Gy (IP BPA-F, n = 8), respectively. The median survival of the untreated controls was 22 days. The median survival of the rats treated with 22.5 Gy of 250 kVp X rays (n = 23) was 35 days with 20% long-term survivors. Fifty percent of the rats in the IG BPA + thermal neutrons group survived over 1 year. All rats in both groups that received IP BPA-F + thermal neutrons have survived over 8 months. Magnetic resonance imaging of the brains of the long-term boron neutron capture therapy survivors showed a scar at the site of tumor implantation in all animals. In the IP BPA-F high-dose group one rat showed evidence of edema and one rat showed a fluid-filled cyst replacing the tumor. CONCLUSION: The use of IP BPA-F has significantly improved long-term survival compared to IG BPA. The high percentage of long-term tumor control (100%, n = 16) in the intracerebral rat 9L gliosarcoma brain tumor model, together with little or no damage to the surrounding normal brain in the majority of surviving animals, demonstrate the substantial therapeutic gain produced by boron neutron capture therapy.

Animals↗
PubMed1994

A nude rat model for neutron capture therapy of human intracerebral melanoma.

PURPOSE: The present study was carried out to determine the efficacy of Boron Neutron Capture Therapy (BNCT) for intracerebral melanoma using nude rats, the human melanoma cell line MRA 27, and boronophenylalanine as the capture agent. METHODS AND MATERIALS: Pharmacokinetic and tissue distribution studies: MRA 27 cells (2 x 10(5)) were implanted intracerebrally, and 30 days later, 120 mg of 10B-L-BPA were injected intraperitoneally into nude rats. Therapy experiments: Thirty days following implantation, tumor bearing rats were irradiated at the Brookhaven Medical Research Reactor. RESULTS: Pharmacokinetic experiments: Six hours following administration of BPA, tumor, blood, and normal brain boron-10 levels were 23.7, 9.4, and 8.4 micrograms/g respectively. Therapy experiments: Median survival time of untreated rats was 44 days compared to 76 days and 93 days for those receiving physical doses of 2.73 Gy and 3.64 Gy, respectively. Rats that had received both 10B-BPA and physical doses of 1.82, 2.73, or 3.64 Gy had median survival times of 170, 182, and 262 days, respectively. Forty percent of rats that had received the highest tumor dose (10.1 Gy) survived for > 300 days and in a replicate experiment 21% of the rats were longterm survivors (> 220 days). Animals that received 12 Gy in a single dose or 18 Gy fractionated (2 Gy x 9) of gamma photons from a 137Cs source had median survival times of 86 and 79 days, respectively, compared to 47 days for untreated animals. Histopathologic examination of the brains of longterm surviving rats, euthanized at 8 or 16 months following BNCT, showed no residual tumor, but dense accumulations of melanin laden macrophages and minimal gliosis were observed. CONCLUSION: Significant prolongations in median survival time were noted in nude rats with intracerebral human melanoma that had received BNCT thereby suggesting therapeutic efficacy. Large animal studies should be carried out to further assess BNCT of intracerebral melanoma before any human trials are contemplated.

Animals↗
PubMed1994

Radiation effects of boron neutron capture therapy on brain, skin, and eye of rats.

PURPOSE: The present study was carried out to evaluate the radiation effects of boron neutron capture therapy (BNCT) on the brain, skin, and eyes of nude rats following systemic administration of boronophenylalanine (BPA) and neutron irradiation to the head. METHODS AND MATERIALS: A solution containing 120 mg of 10B-enriched-L-BPA complexed with fructose was administered IP to nude rats. Boron concentrations were approximately 8.4, 9.4, 10.0, and 11.0 micrograms/g in the brain, blood, skin, and eyes, respectively, at 6 h when the animals were irradiated at the Brookhaven Medical Research Reactor (BMRR). As determined in a study carried out in parallel with this one, the BNCT radiation doses were sufficient to cause tumor regression in nude rats carrying intracerebral implants of the human melanoma cell line MRA 27. RESULTS: Mild to moderate increases in loose fibrous tissue were observed in the choroid plexus at estimated physical doses to the brain and blood that ranged from 4.3-7.1 Gy and 4.6-7.7 Gy, respectively, and these appeared to be dose and time dependent. Other changes in the choroid plexus included occasional infiltrates of macrophages and polymorphonuclear leukocytes and vacuolation of epithelial cells. Dose-dependent moist desquamation of the skin was observed in all rats, but this had healed by 28 days following irradiation. Cataracts and keratitis developed in the eyes of most animals, and these were dose dependent. CONCLUSION: The minimal histopathological changes seen in the brain at doses that were sufficient to eradicate intracerebral melanoma indicates that BNCT has the potential to cure a tumor bearing host without producing the normal brain injury usually associated with conventional external beam radiation therapy. Studies in canines, which currently are in progress, should further define the dose-effect relationships of BNCT on critical neuroanatomic structures within the brain.

Animals↗
PubMed1994

Strategy for boron neutron capture therapy against tumor cells with over-expression of the epidermal growth factor-receptor.

PURPOSE: Gliomas, squamous carcinomas and different adenocarcinomas from breast, colon and prostate might have an increased number of epidermal growth factor (EGF) receptors. The receptors are, in these cases, candidates for binding of receptor specific toxic conjugates that might inactivate cellular proliferation. The purpose of this study was to evaluate whether it is reasonable to try ligand-dextran based conjugates for therapy. METHODS AND MATERIALS: EGF or TGF alpha were conjugated to dextran and binding, internalization, retention and degradation of eight types of such conjugates were analyzed in EGF-receptor amplified glioma cells. The conjugates were labelled with radioactive nuclides to allow detection and two of the conjugates were carrying boron in the form of carboranyl amino acids or aminoalkyl-carboranes. Comparative binding tests, applying 125I-EGF, were made with cultured breast, colon and prostate adenocarcinoma, glioma and squamous carcinoma cells. Some introductory tests to label with 76Br for positron emission tomography and with 131I for radionuclide therapy were also made. RESULTS: The dextran part of the conjugates did not prevent receptor specific binding. The amount of receptor specific binding varied between the different types of conjugates and between the tested cell types. The dextran part improved intracellular retention and radioactive nuclides were retained for at least 20-24 h. The therapeutical effect improved when 131I was attached to EGF-dextran instead of native EGF. CONCLUSION: The improved cellular retention of the ligand-dextran conjugates is an important property since it gives extended exposure time when radionuclides are applied and flexibility in the choice of time for application of neutrons in boron neutron capture therapy (BNCT). It is possible that ligand-dextran mediated BNCT might allow, if the applied neutron fields covers rather wide areas around the primary tumor, locally spread cells that otherwise would escape treatment to be inactivated.

Adenocarcinoma↗
PubMed1992

4-Borono-2-[18F]fluoro-D,L-phenylalanine: a possible tracer for melanoma diagnosis with PET.

The potential of 4-borono-2-[18F]fluoro-D,L-phenylalanine ([18F]FBPA), a flurodinated derivative of a target compound for boron neutron capture therapy, for melanoma imaging by positron emission tomography (PET) was studied using animal models. A high uptake of [18F]FBPA was found in murine B16 melanoma or in Greene's melanoma No. 179, a melanotic cell line in hamsters, for the first 6 h after injection. Whole body autoradiography using [18F]FBPA gave a clear image of the B16 tumor. The acid-insoluble 18F in the B16 increased to 27% by 6 h, and most of the free 18F was detected as [18F]FBPA in both B16 and plasma. In the hamster models, No. 179 showed a 1.7 times higher uptake than amelanotic Greene's melanoma No. 178 at 6 h post-injection, although both melanomas indicated similar metabolic activities when examined by a tracer uptake study using L-[14C]methionine, 2-deoxy-D-[14C]glucose and [3H]thymidine. [18F]FBPA may be a very promising PET tracer for melanoma imaging.

Animals↗
PubMed1996

Fast neutron radiotherapy and boron neutron capture therapy: application to a human melanoma test system.

Fast neutron radiotherapy has proven to be an effective form of treatment in a selected subset of tumors (salivary gland tumors, sarcomas, and locally-advanced prostate cancer), but has not proven to be more beneficial than conventional photon irradiation for the majority of tumor types upon which it has been tested. Normal tissue tolerance limits preclude simply further escalating the neutron dose. Boron neutron capture (BNC) provides a way of selectively augmenting the radiation dose to the tumor. This process is described, and cell culture and animal model data reviewed. An irradiation configuration was developed where an enhancement of 2.10(-3) for 1 microgram of 10B per gram of tissue was achieved. This is similar to the enhancement achievable in the center of a 20 x 20 cm field envisioned for future applications such as metastases in the brain. A boron concentration of 50 micrograms per gram of tumor tissue leads to a 10% increase in the delivered physical dose in this scenario. The first human test of BNC enhancement of a fast neutron radiotherapy beam using pharmacologically-acceptable doses of orally-administered, 10B-enriched, L-paraboronophenylalanine is reported. An enhancement of tumor response was demonstrated for a melanoma skin nodule test system. Boron levels achieved in blood, skin, and tumors are presented. Future research plans are discussed.

Administration, Oral↗
PubMed2004

Biodistribution of p-borophenylalanine (BPA) in dogs with spontaneous undifferentiated thyroid carcinoma (UTC).

Human undifferentiated thyroid carcinoma (UTC) is a very aggressive tumor which lacks an adequate treatment. The UTC human cell line ARO has a selective uptake of BPA in vitro and after transplanting into nude mice. Applications of boron neutron capture therapy (BNCT) to mice showed a 100% control of growth and a 50% histological cure of tumors with an initial volume of 50 mm(3) or less. As a further step towards the potential application in humans we have performed the present studies. Four dogs with diagnosis of spontaneous UTC were studied. A BPA-fructose solution was infused during 60 min and dogs were submitted to thyroidectomy. Samples of blood and from different areas of the tumors (and in one dog from normal thyroid) were obtained and the boron was determined by ICP-OES. Selective BPA uptake by the tumor was found in all animals, the tumor/blood ratios ranged between 2.02 and 3.76, while the tumor/normal thyroid ratio was 6.78. Individual samples had tumor/blood ratios between 8.36 and 0.33. These ratios were related to the two histological patterns observed: homogeneous and heterogeneous tumors. We confirm the selective uptake of BPA by spontaneous UTC in dogs and plan to apply BNCT in the future.

Animals↗
PubMed2004

The effect of dexamethasone on the uptake of p-boronophenylalanine in the rat brain and intracranial 9L gliosarcoma.

The steroid dexamethasone sodium phosphate (DEX) is routinely used to treat edema in brain tumor patients. The objective of the present study was to evaluate the effects of DEX on the uptake of boronophenylalanine (BPA) using the rat 9L gliosarcoma tumor model and surrounding brain tissue. Two steroid dosage protocols were used. The high-dose DEX protocol involved five 3mg/kg intraperitoneal injections at 47, 35, 23, 11 and 1 h prior to the administration of the BPA for a total dose of 15 mg DEX/kg rat. The low-dose DEX administration protocol involved two doses of 1.5mg/kg at 17 h and 1h prior to BPA injection for a total dose of 3mg DEX/kg rat. The control animals received no pretreatment, prior to the administration of BPA. Seventeen days after tumor implantation, rats were injected i.p. with 0.014 ml/g body weight BPA solution (1200 mg BPA/kg; approximately 59 mg (10)B/kg). In all groups, rats were euthanized at 3h after BPA injection. Administration of the steroid had an effect on tumor weight, which decreased to approximately 78% (p > 0.05) of the control weight in the low-dose DEX group, and approximately 48% (p < 0.001) of the control weight in the high-dose DEX group. At 3 h after the administration of BPA, the concentration of boron in tumor was comparable (p > 0.1) in the control and high-dose DEX groups. The lowest mean value (73.8+/-1.6 microg/g) was obtained in the low-dose DEX group. This was significantly lower (p > 0.02) than the tumor boron contents in the high-dose DEX and control groups, which were 81.1+/-1.9 and 79.9+/-1.7 microg/g, respectively. Tumor:blood boron partition ratios for the control, low- and high-dose DEX groups were 2.3, 2.3 and 2.5, respectively. Boron concentrations were also measured in the normal brain and in the zone of brain adjacent to the tumor exhibiting edema. Although treatment with DEX had no appreciable effect on boron uptake in the normal brain of the rat, after the administration of BPA, it did impact on the boron levels in the zone of peritumoral edema. After the high-dose DEX administration protocol, boron levels in the zone of edema were reduced by approximately 14% (p < 0.02). This finding suggests that BPA targeting of tumor cells in the peritumoral zone could be compromised by DEX. These cells appear to play a critical role in tumor recurrence after BNCT or conventional radiotherapy.

Animals↗
PubMed2004

Preliminary treatment planning and dosimetry for a clinical trial of neutron capture therapy using a fission converter epithermal neutron beam.

A Phase I/II clinical trial of neutron capture therapy (NCT) was conducted at Harvard-MIT using a fission converter epithermal neutron beam. This epithermal neutron beam has nearly ideal performance characteristics (high intensity and purity) and is well-suited for clinical use. Six glioblastoma multiforme (GBM) patients were treated with NCT by infusion of the tumor-selective amino acid boronophenylalanine-fructose (BPA-F) at a dose of 14.0 g/m(2) body surface area over 90 min followed by irradiation with epithermal neutrons. Treatments were planned using NCTPlan and an accelerated version of the Monte Carlo radiation transport code MCNP 4B. Treatments were delivered in two fractions with two or three fields. Field order was reversed between fractions to equalize the average blood boron concentration between fields. The initial dose in the dose escalation study was 7.0 RBEGy, prescribed as the mean dose to the whole brain volume. This prescription dose was increased by 10% to 7.7 RBEGy in the second cohort of patients. A pharmacokinetic model was used to predict the blood boron concentration for determination of the required beam monitor units with good accuracy; differences between prescribed and delivered doses were 1.5% or less. Estimates of average tumor doses ranged from 33.7 to 83.4 RBEGy (median 57.8 RBEGy), a substantial improvement over our previous trial where the median value of the average tumor dose was 25.8 RBEGy.

Aged↗
PubMed2004

Tolerance of normal human brain to boron neutron capture therapy.

Data from the Harvard-MIT and the BNL Phase I and Phase I/II clinical trials, conducted between 1994 and 1999, have been analyzed and combined, providing the most complete data set yet available on the tolerance of the normal human brain to BPA-mediated boron neutron capture therapy. Both peak (1cm(3)) dose and average whole-brain dose show a steep dose-response relationship using somnolence syndrome as the clinical endpoint. Probit analysis indicates that the doses associated with a 50% incidence for somnolence (ED(50)+/-SE) were 6.2+/-1.0 Gy(w) for average whole-brain dose and 14.1+/-1.8 Gy(w) for peak brain dose.

Boron Compounds↗
PubMed2004

Biodistribution studies of boronophenylalanine-fructose in melanoma and brain tumor patients in Argentina.

A study of the (10)B-enriched p-boronophenylalanine-fructose complex ((10)BPA-F) infusion procedure in potential BNCT patients, including four melanoma of extremities and two high-grade gliomas (glioblastoma and ganglioglioma) was performed. T/B and S/B ratios for (10)B concentrations in tumor (T), blood (B) and skin (S) were determined. The T/B ratio for the glioblastoma was in the 1.8-3.4 range. The ganglioglioma did not show any significant boron uptake. For the nodular metastasic melanoma T/B values were between 1.5 and 2.6 (average 2.1+/-0.4), corresponding to the lower limit of the mean values reported for different melanoma categories. This result might suggest a lower boron uptake for nodular metastasic melanomas. S/B was 1.5+/-0.4. An open two-compartment pharmacokinetic model was applied to predict the boron concentration during the course and at the end of a BNCT irradiation.

Adult↗
PubMed2004

Radiobiology of BNCT mediated by GB-10 and GB-10+BPA in experimental oral cancer.

We previously reported biodistribution and pharmacokinetic data for GB-10 (Na(2)(10)B(10)H(10)) and the combined administration of GB-10 and boronophenylalanine (BPA) as boron delivery agents for boron neutron capture therapy (BNCT) in the hamster cheek pouch oral cancer model. The aim of the present study was to assess, for the first time, the response of hamster cheek pouch tumors, precancerous tissue and normal tissue to BNCT mediated by GB-10 and BNCT mediated by GB-10 and BPA administered jointly using the thermalized epithermal beam of the RA-6 Reactor at the Bariloche Atomic Center. GB-10 exerted 75.5% tumor control (partial+complete remission) with no damage to precancerous tissue around tumor or to normal tissue. Thus, GB-10 proved to be a therapeutically efficient boron agent in this model despite the fact that it is not taken up selectively by oral tumor tissue. GB-10 exerted a selective effect on tumor blood vessels leading to significant tumor control with a sparing effect on normal tissue. BNCT mediated by the combined administration of GB-10 and BPA resulted in a reduction in the dose to normal tissue and would thus allow for significant escalation of dose to tumor without exceeding normal tissue tolerance.

Animals↗
PubMed2004

BNCT of 3 cases of spontaneous head and neck cancer in feline patients.

Having demonstrated BPA-BNCT induced control of experimental squamous cell carcinomas (SCC) of the hamster cheek pouch mucosa with no damage to normal tissue we explored the feasibility and safety of treating spontaneous head and neck tumors, with particular focus on SCC, of terminal feline patients with low dose BPA-BNCT employing the thermal beam of the RA-1 Reactor within a preclinical context. The biodistribution studies showed that, in all three cases evaluated, BPA delivered absolute boron values to tumor in the range that proved therapeutically useful in the experimental model of SCC. BPA-BNCT studies showed no radiotoxic effects, partial tumor control in terms of impaired growth and partial necrosis, an improvement in clinical condition and prolonged survival beyond the terminal condition of the feline patients at the time of recruitment.

Animals↗
PubMed2004

Boron biodistribution in beagles after intravenous infusion of 4-dihydroxyborylphenylalanine-fructose complex.

Boron biodistribution after intravenous infusion of 4-dihydroxyborylphenylalanine-fructose (BPA-F) complex was investigated in six dogs. Blood samples were evaluated during and following doses of 205 and 250 mg/kgbw BPA in a 30 min infusion, and 500 mg/kgbw in a 1h infusion. Samples from whole blood, urine, brain and other organs were analysed for boron content after varying times following the onset of infusion. The whole blood boron concentrations declined from 27 to 8.4 ppm over the period of 39-165 min after the onset of infusion and the levels increased from 1.9 to 12 ppm in the grey matter of the brain over the same period. The boron concentrations in whole blood decreased steadily, whereas the boron values in brain tissue rose steadily with time. It was concluded that whole blood boron concentrations do not seem to reflect accurately the boron concentration in brain tissue at respective time points.

Animals↗