Neutron capture therapy of the 9l rat gliosarcoma using the P-boronophenylalanine-fructose complex

Coderre, Jeffrey A.; Button, Terry M.; Micca, Peggy L.; Fisher, Craig D.; Nawrocky, Marta M.; Liu, Hungyuan B.

doi:10.1016/0360-3016(92)90951-d

Cited by 131 publications

(54 citation statements)

References 17 publications

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“…Considered overall, the concentration of '°B in the CNS parenchyma increased progressively with time over the 3 h observation period, but was relatively low at all dose levels. Similar observations were made in a previous study (Coderre et al, 1994), in which BPA was administered to an identical strain of rat at a dose of 1200 mg kg-'. In this study, '°B levels (approximately 18 jg g-') in the brain plateaued at 3 to 6 h after BPA administration, and thereafter declined slowly, reaching a level of approximately 5 jig g-after 24 h.…”

Section: Discussionsupporting

confidence: 87%

“…Rats were maintained in a controlled light/dark cycle, with lights on between 07.00 and 19.00 h. p-Boronophenylalanine (BPA) containing 4.9% '0B (Boron Biologicals, Raleigh, NC, USA) was used as the boron delivery agent. The BPA was dissolved in a fructose solution, as described previously (Coderre et al, 1994), and administered by intraperitoneal (i.p.) injection.…”

Section: Methodsmentioning

confidence: 99%

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Central nervous system tolerance to boron neutron capture therapy with p-boronophenylalanine

Morris

Coderre²,

Micca³

et al. 1997

Br J Cancer

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Summary A rat spinal cord model was used to evaluate the effects of boron neutron capture irradiation on the central nervous system (CNS), using a range of doses of the boron delivery agent pboronophenylalanine (BPA). Three doses of BPA 700, 1000 and 1600 mg kg-' were used to establish the biodistribution of boron-10 ('°B) in blood, spinal cord and brain over a 3-h period after intraperitoneal (ip) administration. At the lowest dose of BPA used, blood '°B levels remained relatively stable over the 3-h sampling period. With the two higher doses of BPA, blood '°B concentrations were greatest at 1 h after BPA administration, and thereafter exhibited a biphasic clearance profile. The largest decline in blood '°B levels occurred between 1 and 2 h after ip injection and was most pronounced (approximately 45%) in the highest BPA dose group. Considered overall, '°B concentrations were marginally lower in the spinal cord than in the brain. Levels of 10B in both of these organs showed a slow but progressive increase with time after administration of BPA. The '°B concentration ratio for blood relative to CNS tissue increased with BPA dosage and reached a peak value of approximately 10:1 in the highest BPA dose group, at 1 h after ip injection. However, at 3 h after injection the 10B concentration ratios had decreased to approximately 3:1 in all of the BPA dose groups. After irradiation with thermal neutrons in combination with BPA at blood '°B concentrations of approximately 42 and approximately 93 gig g-1, myelopathy developed after latent intervals of 20.0 ± 0.6 and 20.0 ± 1.2 weeks respectively. ED50 values (+ s.e.) for the incidence of myelopathy were calculated from probitfitted curves, and were 17.5 ± 0.7 and 25.0 ± 0.6 Gy after irradiation with thermal neutrons at blood '°B levels of approximately 42 and approximately 93,g g-1 respectively. The compound biological effectiveness (CBE) factor values, estimated from these data, were 0.67 ± 0.23 and 0.48 ± 0.18 respectively. This compared with a previous estimate of 0.88 ± 0.14 at a blood '°B concentration of approximately 19 gg g-'. It was concluded that the value of the CBE factor was not influenced by the level of '°B in the blood, but by the blood:CNS '°B concentration ratio. In effect, the CBE factor decreases as the concentration ratio increases. Simulations using boron neutron capture therapy (BNCT) treatment planning software indicate a significant therapeutic advantage could be obtained in moving to higher BPA doses than those in current clinical use.

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Central nervous system tolerance to boron neutron capture therapy with p-boronophenylalanine

Morris

Coderre²,

Micca³

et al. 1997

Br J Cancer

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“…18 Use of an ion exchange resin in place of a mineral acid precludes the presence of salt in the solution and thus facilitates the isolation of the L-p-BPAfructose complex. Furthermore, this "salt-free" method offers a clinically significant advantage over the current method for the preparation of the L-BPA-fructose complex because the current method 19 is accompanied by up to a full equivalent of NaCl, thus greatly exceeding its isosmotic point with blood. It was determined that when complex formation is strong (such as for fructose and sorbose) or when a large excess of another carbohydrate is used, at a pH of 7.4 all the L-p-BPA remains in solution and approximately 90% of the L-p-BPA is present as its sodium salt, with the remainder as its free acid.…”

Section: Resultsmentioning

confidence: 97%

Studies on the Structure of the Complex of the Boron Neutron Capture Therapy Drug, L‐p‐Boronophenylalanine, with Fructose and Related Carbohydrates: Chemical and 13C NMR evidence for the β‐D‐Fructofuranose 2,3,6‐(p‐Phenylalanylorthoboronate) Structure

Shull

Spielvogel²,

Head³

et al. 2000

Journal of Pharmaceutical Sciences

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“…In comparison, the median survival of rats bearing the same gliosarcoma and treated with 22.5 Gy of 250 kVp X rays was 35 days, with only 20% long-term (i.e., Ͼ70 to approx. 365 days) survivors (Coderre et al, 1994). Neutron-capture therapy of the same gliosarcoma with the p-boronophenylalanine-fructose complex (absorbed physical dose to tumor 15.5 Gy) yields more than 50% long-term survivors with little or no damage to the surrounding normal brain (Coderre et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X rays

et al. 1998

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Adult‐rat‐brain tissues display an unusually high resistance to necrosis when serially irradiated with parallel, thin slices of a microplanar (i.e., microscopically thin and macroscopically broad) beam of synchrotron‐wiggler‐generated, approx. 35–120 keV (median approx. 50 keV) Gd‐filtered X rays at skin‐entrance absorbed doses of 312 to 5000 Gy per slice. Such microplanar beams were used to irradiate young adult rats bearing right frontocerebral 9L gliosarcomas (approx. 4 mm diameter), through a volume of tissue containing the tumor and contiguous brain tissue, either in a single array or in 2 orthogonally crossed arrays of tissue slices. Each array included 101 parallel microplanar slices, 100 μm center‐to‐center distance, each slice being approx. 25 μm wide and 12 mm high, with skin‐entrance absorbed doses of 312.5 Gy or 625 Gy per slice. Compared with unirradiated controls with a median survival time of 20 days after tumor initiation, the median survival time was extended in irradiated rats by 139 days (625 Gy, crossed arrays), 96 days (312.Gy, crossed arrays) or 24 days (625 Gy, single array). The tumors disappeared in 22 of the 36 irradiated rats, 4/ 11 even after unidirectional microbeam irradiation. The extent and severity of radiation damage to the normal brain in rats with or without tumor was graded histopathologically. Correlation of those grades with radiation doses shows that loss of tissue structure was confined to beam‐crossing regions and that only minor damage was done to zones of the brain irradiated unidirectionally. Int. J. Cancer 78:654–660, 1998. © 1998 Wiley‐Liss, Inc.

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Neutron capture therapy of the 9l rat gliosarcoma using the P-boronophenylalanine-fructose complex

Cited by 131 publications

References 17 publications

Central nervous system tolerance to boron neutron capture therapy with p-boronophenylalanine

Central nervous system tolerance to boron neutron capture therapy with p-boronophenylalanine

Studies on the Structure of the Complex of the Boron Neutron Capture Therapy Drug, L‐p‐Boronophenylalanine, with Fructose and Related Carbohydrates: Chemical and 13C NMR evidence for the β‐D‐Fructofuranose 2,3,6‐(p‐Phenylalanylorthoboronate) Structure

Neuropathology of ablation of rat gliosarcomas and contiguous brain tissues using a microplanar beam of synchrotron-wiggler-generated X rays

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