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Biomedical subjects

D N Slatkin

Publications and source records attributed to D N Slatkin.

At least 37 records · Page 2Linked to original sources
PubMed1995

Subacute neuropathological effects of microplanar beams of x-rays from a synchrotron wiggler.

Microplanar beam radiation therapy has been proposed to treat brain tumors by using a series of rapid exposures to an array of parallel x-ray beams, each beam having uniform microscopic thickness and macroscopic breadth (i.e., microplanar). Thirty-six rats were exposed head-on either to an upright 4-mm-high, 20- or 37-microns-wide beam or to a horizontal 7-mm-wide, 42-microns-high beam of mostly 32- to 126-keV, minimally divergent x-rays from the X17 wiggler at the National Synchrotron Light Source at Brookhaven National Laboratory. Parallel slices of the head, separated at either 75 or 200 microns on center, were exposed sequentially at 310-650 grays (Gy) per second until each skin-entrance absorbed dose reached 312, 625, 1250, 2500, 5000, or 10,000 Gy. The rats were euthanized 2 weeks or 1 month later. Two rats with 10,000-Gy-entrance slices developed brain tissue necrosis. All the other 10,000- and 5000-Gy-entrance slices and some of the 2500- and 1250-Gy-entrance slices showed loss of neuronal and astrocytic nuclei and their perikarya. No other kind of brain damage was evident histologically in any rat with entrance absorbed doses < or = 5000 Gy. Brain tissues in and between all the 312- and 625-Gy-entrance slices appeared normal. This unusual resistance to necrosis is central to the rationale of microplanar beam radiation therapy for brain tumors.

Animals↗
PubMed1994

Improved apparatus for neutron capture therapy of rat brain tumors.

PURPOSE: The assembly for irradiating tumors in the rat brain at the thermal neutron beam port of the Brookhaven Medical Research Reactor was redesigned to lower the average whole-body dose from different components of concomitant radiation without changing the thermal neutron fluence at the brain tumor. METHODS AND MATERIALS: At present, the tumor-bearing rat is positioned in a rat holder that functions as a whole-body radiation shield. A 2.54 cm-thick collimator with a centered conical aperture, 6 cm diameter tapering to 2 cm diameter, is used to restrict the size of the thermal neutron field. Using the present holder and collimator as a baseline design, Monte Carlo calculations and mixed-field dosimetry were used to assess new designs. RESULTS: The computations indicate that a 0.5 cm-thick plate, made of 6Li2CO3 dispersed in polyethylene (Li-poly), instead of the existing rat holder, will reduce the whole-body radiation dose. Other computations show that a 10.16 cm-thick (4 inches) Li-poly collimator, having a centered conical aperture of 12 cm diameter tapering to 2 cm diameter, would further reduce the whole-body dose. CONCLUSION: The proposed irradiation apparatus of tumors in the rat brain, although requiring a 2.3-fold longer irradiation time, would reduce the average whole-body dose to less than half of that from the existing irradiation assembly.

Animals↗
PubMed1993

Derivations of relative biological effectiveness for the high-let radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo.

PURPOSE: Relative biological effectiveness (RBE) values for the high linear-energy-transfer particles produced during boron neutron capture therapy have generally been based on theoretical considerations or in vitro experiments. The purpose of this study was to independently determine RBE values for all of the boron neutron capture therapy dose components. METHODS AND MATERIALS: Clonogenic cell survival data were obtained for 9L rat gliosarcoma cells irradiated in the Brookhaven Medical Research Reactor thermal neutron beam both in vitro and as an intracerebral tumor. These data were analyzed using the linear quadratic model for cell survival to derive measured RBE values for all beam components and for a number of different boron compounds. RESULTS: In the absence of boron, the combined effects of the protons from the nitrogen capture, 14N(n,p)14C, and the fast neutron scatter, 1H(n,n')p, reactions generated RBEs of 3.7 in vitro and 3.2 in an in vivo/in vitro excision assay, compared to 250 kVp X rays using an end point of 1% cell survival. Apparent RBEs for the 10B(n,alpha)7Li reaction products were calculated from cell survival data following reactor irradiations in the presence of the amino acid p-boronophenylalanine, the sulfhydryl dodecaborate monomer or dimer, or boric acid. Apparent RBEs for the 10B(n,alpha)7Li reaction ranged from 1.2 to 9.8 depending on which boron compound was used. RBEs from the in vitro studies were consistently higher than from the in vivo/in vitro studies. Under any conditions, the apparent RBE for the 10B(n,alpha)7Li reaction with p-boronophenylalanine was higher than that with any other boron compound tested. CONCLUSIONS: Generally accepted RBE values for the fast neutron and 14N(n,p)14C reaction components of the total dose are too low. The apparent RBEs calculated for the 10B(n,alpha)7Li reaction were compound-dependent and consistent with differences in the distribution of 10B relative to glioma cell nuclei.

Animals↗
PubMed1993

A commentary on in vivo lead X-ray fluorescence with reference to the 1992 workshop.

One of the main purposes of this Commentary is to respond to some of the issues raised in a Summary by Todd et al. (1993) of the 1992 Workshop sponsored by the National Institute of Environmental Health Sciences on X-Ray Fluorescence (XRF), as it contains apparently undocumented claims for K-Line XRF (KXRF) techniques and understates the efficacy and clinical research results of the L-Line XRF (LXRF) technique (Rosen et al., 1989; Rosen et al., 1991). This Commentary presents a point of view concerning the Workshop that is different in several respects from that published by Todd, Landrigan and Bloch (Todd et al., 1993). As two of the three co-developers of the L-Line XRF (LXRF) technique, we wish to draw the following information to the attention of readers of Neurotoxicology, some of which was published before the Workshop took place and some of which has been published subsequently (Rosen et al., 1993; Rosen and Markowitz, 1993; Markowitz et al., 1993).

Environmental Health↗
PubMed1992

Biodistribution and toxicity of 2,4-divinyl-nido-o-carboranyldeuteroporphyrin IX in mice.

BALB/c mice with transplanted subcutaneous KHJJ mammary carcinomas were given 2,4-divinyl-nido-o-carboranyldeuteroporphyrin IX (VCDP), a prospective boron carrier for boron neutron-capture therapy, to determine the dose schedule that results in maximal boron uptake in tumor. A total dose of 270 +/- 10 micrograms/g body weight given in a 4-day multiple intraperitoneal injection schedule (3/day) resulted in 30-50 micrograms boron/g tumor. After such a dose, thrombocytopenia, granulocytosis and altered liver enzyme levels were measured in the blood. Blood boron clearance was followed for an 18 hr to 6 day post-injection period. Toxic effects of VCDP subsided within 4-6 days after the last injection. In view of the greater than 30 micrograms/g peak accumulation of boron in tumor from VCDP and the subsequent rapid reversal of VCDP toxicity, further studies of VCDP in small mammals relevant to its distribution, toxicity and potential clinical use for neutron-capture therapy of tumors appear warranted.

Animals↗
PubMed1992

Control of intracerebral gliosarcomas in rats by boron neutron capture therapy with p-boronophenylalanine.

Boron neutron capture therapy (BNCT) of transplanted intracerebral GS-9L rat gliosarcomas was effected by irradiation at a nuclear reactor, primarily with thermal neutrons, after two intragastric doses of p-boronophenylalanine (BPA). At the time of BNCT, tumor 10B levels were approximately 40 micrograms 10B/g with tumor:blood and tumor:brain 10B concentration ratios of about 3.3:1 and 3.9:1, respectively. This resulted in calculated doses to tumor that were approximately 2.3-fold greater than those to normal brain parenchyma and brain vascular endothelium within the treatment volume. Approximately 75% of the tumor dose resulted from the 10B(n,alpha)7Li nuclear reaction. The median survival of untreated rats (n = 20) was 20 days after initiation of tumors. Reactor irradiation only (no BPA) increased the median survival to 25 days (n = 25). None of the rats in the untreated or irradiation-only groups survived longer than 34 days after initiation of tumors. Two BNCT dose levels were used: 8.9 Gy (19.3 Gy x relative biological effectiveness, or Gy-eq) and 13.4 Gy (29.0 Gy-eq). The median post-BNCT survivals of BPA-treated rats in the 8.9-Gy (n = 16) and 13.4-Gy (n = 12) groups were 60 and 120 days, respectively, including seven long-term (greater than 12 months) survivors at 8.9 Gy and six long-term (greater than 5 months) survivors at 13.4 Gy. Survival times following BPA-based BNCT (either 8.9 or 13.4 Gy) were significantly longer than those following 250-kVp X-ray doses of 15 Gy (n = 24), 22.5 Gy (n = 32) or 30 Gy (n = 26).

Animals↗
PubMed1991

In vivo boron-11 MRI and MRS using (B24H22S2)4- in the rat.

In vivo boron-11 magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were performed on a rat that had been infused with a potential boron neutron capture therapy agent, Na4B24H22S2, using methods for detecting nuclei with a short T2 relaxation time. MRI and MRS were also performed on a euthanized rat that had been similarly infused in vivo. Boron-11 spectral intensities decreased in the living rat over a 25-h period. The results demonstrate the capability of MRI and MRS to noninvasively monitor the distribution and excretion of boron agents in vivo.

Animals↗
PubMed1991

A history of boron neutron capture therapy of brain tumours. Postulation of a brain radiation dose tolerance limit.

Boron neutron capture therapy (BNCT) is a form of radiation therapy mediated by the short-range (less than 10 microns) energetic alpha (4He) and lithium-7 (7Li) ionizing particles that result from the prompt disintegration by slow neutrons of the stable (nonradioactive) nucleus boron-10 (10B). Recent advances in radiobiological and toxicological evaluation of tumour-affinitive boron-containing drugs and in optimization of the energies of neutrons in the incident beam have spurred interest in BNCT. This article presents a history of BNCT that emphasizes studies in the USA. A new dosimetric analysis of the 1959-1961 clinical trials of BNCT at Brookhaven National Laboratory is also presented. This analysis yields an acute radiation dose tolerance limit estimate of approximately 10 Gy-Eq to the capillary endothelium of human basal ganglia from BNCT. (Gy-Eq: Gray-equivalent, or relative biological effectiveness of a radiation component multiplied by the physical dose of the component (Gy), summed over the component kinds of radiation.)

Boron↗
PubMed1991

Sequential measurements of bone lead content by L X-ray fluorescence in CaNa2EDTA-treated lead-toxic children.

With the development of L X-ray fluorescence (LXRF) to measure cortical bone lead directly, safely, rapidly, and noninvasively, the present study was undertaken to a) evaluate LXRF as a possible replacement for the CaNa2EDTA test; b) quantify lead in tibial cortical bones of mildly to moderately lead-toxic children before treatment; and c) quantify lead in tibial cortical bones of lead-toxic children sequentially following one to two courses of chelation therapy. The clinical research design was based upon a longitudinal assessment of 59 untreated lead-toxic children. At enrollment, if the blood lead (PbB) was 25 to 55 micrograms/dL and the erythrocyte protoporphyrin (EP) concentration was greater than or equal to 35 micrograms/dL, LXRF measurement of tibial bone lead was carried out. One day later, each child underwent a CaNa2EDTA provocative test. If this test was positive, lead-toxic children were admitted to the hospital for 5 days of CaNa2EDTA therapy. These tests were repeated 6 weeks and 6 months after enrollment. Abatement of lead paint hazards was achieved in most apartments by the time of initial hospital discharge. The LXRF instrument consists of a low energy X-ray generator with a silver anode, a lithium-doped silicon detector, a polarizer of incident photons, and a multichannel X-ray analyzer. Partially polarized photons are directed at the subcutaneous, medial mid-tibial cortical bone. The LXRF spectrum, measured 90 degrees from the incident beam, reveals a peak in the 10.5 KeV region, which represents the lead L alpha line.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone and Bones↗
PubMed1991

Sequential measurements of bone lead content by L X-ray fluorescence in CaNa2EDTA-treated lead-toxic children.

With the development of L X-ray fluorescence (LXRF) to measure cortical bone lead directly, safely, rapidly, and noninvasively, the present study was undertaken to a) evaluate LXRF as a possible replacement for the CaNa2EDTA test; b) quantify lead in tibial cortical bones of mildly to moderately lead-toxic children before treatment; and c) quantify lead in tibial cortical bones of lead-toxic children sequentially following one to two courses of chelation therapy. The clinical research design was based upon a longitudinal assessment of 59 untreated lead-toxic children. At enrollment, if the blood lead (PbB) was 25 to 55 micrograms/dL and the erythrocyte protoporphyrin (EP) concentration was greater than or equal to 35 micrograms/dL, LXRF measurement of tibial bone lead was carried out. One day later, each child underwent a CaNa2EDTA provocative test. If this test was positive, lead-toxic children were admitted to the hospital for 5 days of CaNa2EDTA therapy. These tests were repeated 6 weeks and 6 months after enrollment. Abatement of lead paint hazards was achieved in most apartments by the time of initial hospital discharge. The LXRF instrument consists of a low energy X-ray generator with a silver anode, a lithium-doped silicon detector, a polarizer of incident photons, and a multichannel X-ray analyzer. Partially polarized photons are directed at the subcutaneous, medial mid-tibial cortical bone. The LXRF spectrum, measured 90 degrees from the incident beam, reveals a peak in the 10.5 KeV region, which represents the lead L alpha line.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone and Bones↗
PubMed1991

Boron neutron capture therapy of a murine melanoma with p-boronophenylalanine: dose-response analysis using a morbidity index.

Boron-10 concentrations of 20 or 40 micrograms/g were attained in mouse B16 melanomas following one or two intragastric doses of p-boronophenylalanine (750 mg/kg body weight per dose), respectively. Tumor-to-normal-tissue (blood, muscle) boron concentration ratios were 4:1-6:1. The efficacy of boron neutron capture irradiation was monitored using the Wilcoxon two-sample test in conjunction with a system of ranking outcomes of different therapies that compared living mice and mice sacrificed because of excessive tumor growth concomitantly. Median survivals were extended progressively as radiation doses were increased up to 38.7 gray-equivalent (gray X relative biological effectiveness), with one of five and one of six tumors cured in each of the two highest dose groups, respectively. When comparable tumor inhibitory doses of 250-kVp X rays were used to treat these tumors, instead of the transient erythema and edema that resulted from boron neutron capture therapy, there resulted irreversible muscle necrosis in the irradiated zone and atrophy of the foot distal to the irradiated zone. The improvement in treatment outcome with boron neutron capture therapy is attributable to unprecedented tumor-to-normal-tissue radiation dose ratios of approximately 2.8 to 3.6.

Animals↗
PubMed1990

Cyclosporine A inhibition of microcystin toxins.

Cyclosporine A (CyA) given i.v. at a dose of 1.25 mg/mouse blocks a subsequent i.v. lethal dose (1.7-1.8 x LD50) of microcystin-LR for 24 hr, and is about 50% protective at 48 hr. Conversely, the fraction of mice that can be rescued by CyA (0.2 mg/mouse) after a lethal dose of microcystin-LR decreases rapidly with a pharmacodynamic half-time of only about 100 sec. The prophylactic action of CyA was tested against lethal doses of four microcystins. The acute lethality of 1.7-1.8 x LD50 dose of microcystin-LR, -RR, -LY, or -LA given 1 hr after administration of 0.2 mg of CyA is 0%, 0%, 58%, or 100%, respectively. Even a 0.6 mg/mouse dose of CyA is ineffective prophylaxis against a lethal dose of microcystin-LA. The inhibitory potency of CyA on microcystin toxicity can be completely reversed by the single L-amino acid substitution of alanine for arginine in the microcystin.

Animals↗
PubMed1990

Uptake of a nido-carboranylporphyrin by human glioma xenografts in athymic nude mice and by syngeneic ovarian carcinomas in immunocompetent mice.

A tetraphenylporphyrin bearing four dicarbollide ([B9C2H11]-) cages linked to the o-phenyl ring positions by anilide bonds, known as boronated tetraphenylporphyrin (BTPP), has been synthesized in excellent yield from tetra-(o-aminophenyl) porphyrin and carborane carbonyl chloride followed by base-assisted cage opening and ion exchange to give the highly water-soluble potassium salt. Preliminary studies showed that BTPP accumulates in liver and in a syngeneic ovarian carcinoma, but not in normal brain parenchyma, of mice infused with BTPP subcutaneously for 6 or 7 days via surgically implanted osmotic minipumps. In this study, the uptake of boron was measured in human gliomas xenografted subcutaneously to athymic nude mice in which BTPP was infused intraperitoneally or subcutaneously or both for 3 or 7 days by using similar minipumps. Immunocompetent mice bearing a syngeneic ovarian carcinoma were similarly infused to provide comparative data. Bulk concentrations of boron up to 18 micrograms/g of glioma and up to 45 micrograms/g of carcinoma were observed when up to 102 micrograms/g of tissue was present in the liver after 7 days of BTPP infusion. Glioma boron concentrations were increased by approximately 80% on the average (up to 33 micrograms/g) when correspondingly greater amounts of BTPP were infused in only 3 days. Cell counts and chemical tests on blood samples from individual mice indicate that BTPP causes moderate hepatotoxicity and thrombocytopenia. This hepatohematic toxicity syndrome should be taken into account if BTPP or a similar agent is used for boron neutron-capture therapy (BNCT) of human malignancies.

Animals↗
PubMed1990

Boron neutron capture therapy of intracerebral rat gliosarcomas.

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.

Animals↗