Brenda H. Laster

Microanalytical techniques for boron analysis using the 10B(n,α)7Li reaction

In order to predict the efficacy of boronated compounds for neutron capture therapy (NCT), it is mandatory that the boron concentration in tissues be known. Various techniques for measurement of trace amounts of boron (1–100 ppm) are available, including chemical and physical procedures. Experience has shown that, with the polyhedral boranes and carboranes in particular, the usual colorimetric and spark emission spectroscopic methods are not reliable. Although these compounds may be traced with additional radiolabels, direct physical detection of boron by nondestructive methods is clearly preferable. Boron analysis via detection of the prompt‐γ ray from the 1 0B(n,α)7Li reaction has been shown to be a reliable technique. Two prompt‐γ facilities developed at Brookhaven National Laboratory are described. One, at the 60‐MW high flux beam reactor, uses sophisticated beam extraction techniques to enhance thermal neutron intensity and reduce fast neutron and γ contamination. The other was constructed at Brookhaven’s 5‐MW medical research reactor and uses conventional shielding and electronics to provide an ‘‘on‐line’’ boron analysis facility adjacent to beams designed for NCT, thus satisfying one of the requisites for clinical application of this procedure. Technical restrictions attendant upon the synthesis and testing of boronated biomolecules often require the measurement of trace amounts of boron in extremely small (mg) samples. A track‐etching technique capable of detecting ng amounts of boron in mg liquid or cell samples is described. Thus it is possible to measure the boron content in small amounts (mg samples) of antibodies, or boron uptake in cellsgrown in tissue culture.

Photon Activation of Iododeoxyuridine: Biological Efficacy of Auger Electrons

Photon activation therapy is a binary system being investigated as a potential therapeutic modality to improve the treatment of malignancies, particularly the highly lethal and malignant brain tumor, glioblastoma multiforme. Its success relies upon the incorporation of a target atom in the immediate vicinity of a tumor cells critical site, followed by the activation of this atom with photons of energies suitable for the induction of the photoelectric effect and its concomitant Auger cascades. The collective action of the Auger electrons imparts high-LET type damage at the critical site. Photon activation therapy uses iodine from stable iododeoxyuridine (IdUrd) as the target atom, and monochromatic photons above the K absorption edge of iodine (33.2 keV) as the activating agent. Although IdUrd is a cell-sensitizing agent, work described was designed to separate the biological efficacy due to sensitization from that of the Auger effect. Chinese hamster V79 cells with and without IdUrd in cellular DNA were irradiated at the X17B1 beam line in the National Synchroton Light Source of Brookhaven National Laboratory. Monochromatic photons above (33.4 keV) and below (32.9 keV) the K absorption edge were used to determine if any additional biological damage would accrue from the Auger cascades. The 33.4-keV photons were found to be a factor of 1.4 times more effective than 32.9-keV photons in damaging iodinated cells. The sensitizing effect, evaluated separately, was found to be a factor of 2.2 at 10% survival, regardless of photon energy. Thus the total therapeutic gain was 1.4 x 2.2 = 3.1. Irradiations of noniodinated control cells showed no difference in their response to energies above and below the iodine K edge.

Installation and Testing of an Optimized Epithermal Neutron Beam at the Brookhaven Medical Research Reactor (BMRR)

NCT is a binary system, in which 10B is physiologically targeted to tumor and then allowed to interact with thermal neutrons generated in the treatment volume by an externally applied neutron beam. Consequently, an unusually large number of parameters are obtained, which bear on the resultant Therapeutic Gain (TG). However, a perusal of these data, as illustrated in Figure 7, indicates that the TG would increase significantly beyond values projected in this paper if the absolute amount of 10B could be increased above 30 ppm. For example, increasing 10B concentration in tumor to 45 ppm would increase TG by approximately 33% (with a T/N of 5). A similar increase in TG would follow an increase in T/N from 5 to 10. Those associated with the development of boron compounds for NCT feel that such developments are within reach.

Epithermal beam development at the BMRR: dosimetric evaluation.

The utilization of an epithermal-neutron beam for neutron capture therapy (NCT) is desirable because of the increased tissue penetration relative to a thermal-neutron beam. Over the past few years, modifications have been and continue to be made at the Brookhaven Medical Research Reactor (BMRR) to produce an optimal epithermal beam by changing filter components. An optimal incident epithermal beam should contain the minimum possible fast-neutron component and no thermal neutrons. Recently, a new moderator for the epithenmal beam was installed at the epithermal port of the BMRR. With the installation of this moderator, an optimal beam has been realized [1]. This new moderator is a combination of alumina (Al2O3) bricks and aluminum (Al) plates. A 0.51-mm thick cadmium (Cd) sheet has reduced the thermal-neutron intensity drastically. Furthermore, an 11.5-cm thick bismuth (Bi) plate installed at the port surface has reduced the gamma-dose component to negligible levels. In order to compare various filter configurations for best optimization [2], the following parameters have been measured on the beam axis, directly in front of the epithermal port: 1) Thermal-neutron fluence rate free in air 2) Epithermal-neutron fluence rate free in air 3) Fast-neutron fluence rate free in air 4) Thermal-neutron fluence rate in a polyethylene cylindrical head phantom as a function of distance along the axis of the phantom 5) Fast-neutron dose rate in soft tissue, free in air, and 6) Gamma-dose rate in soft tissue, free in air.

Samarium-145: a new brachytherapy source

A new radiation source has been produced for brachytherapy, with radiation energies slightly above those of 125I, and a T1/2 of 340 d. This source, 145Sm, is produced by neutron irradiation of 144Sm (96.5% enriched). Decay is by electron capture with 140 K x-rays per 100 disintegrations in the energy region between 38-45 keV, plus 13 gamma-rays at 61 keV. These sources are encapsulated in Ti tubes, approximately 0.8 mm X 4.5 mm, and have been developed for temporary implantation in brain and ocular tumours. The 38-61 keV photons should make such sources easy to shield, while providing a dose distribution from source arrays somewhat more homogeneous than that from 125I. In addition, the 340 d half life of 145Sm permits its use for times significantly longer than that of 60 d 125I. While the 145Sm sources have been designed primarily for implantation in a brain tumour, they should be useful for almost any conventional brachytherapy application.

Distributions of Sulfhydryl Borane Monomer and Dimer in Rodents and Monomer in Humans: Boron Neutron Capture Therapy of Melanoma and Glioma in Boronated Rodents

Boron neutron capture therapy (BNCT), a form of radiation therapy based on the 10B(n,α)7Li nuclear reaction,1,2 has been used in Japan for radiation therapy of human malignant gliomas after total or partial neurosurgical excision of visible tumor.3 Japanese data for 10B distribution in the blood and tumor of 30 patients with malignant glioma have been summarized.4 The stable isotope 10B was introduced into the tumor during a 1–2 hour intra-arterial infusion of a 10B-enriched preparation of the sulfhydryl borane monomer Na2B12H11SH to a total dose in the range 30–80 mg 10B per kg total body weight. The tumor bed was irradiated for 5–7 hours at a 100-kW nuclear reactor, 11 to 16 hours after the infusion. The average tumor 10B concentration just before irradiation was 22 μg 10B/g, while the average blood 10B concentration was 18 μg 10B/g.4 Despite low tumor:blood 10B concentration ratios just before irradiation (average ratio = 1.2:1.0), post-operative survival after BNCT was unexpectedly prolonged for some patients--indeed astonishingly so for a 66-year-old Japanese man who is neurologically and neuroradiologically stable nearly sixteen years after visibly incomplete removal of a malignant glioma.4

The Biological Effects of Auger Electrons Compared to α-Particles and Li Ions

The present study reports the results of V-79 Chinese hamster cell survival studies in which Auger electron emission was stimulated in gadolinium (Gd) after thermal neutron capture. When a porphyrin that had previously been labeled with boron (10BOPP) was also labeled with Gd (Gd-10BOPP), the cells were incubated with Gd-10BOPP to assess the compounds ability to physiologically transport the Gd into the cell, and localize the Gd atoms in or near the cells critical target, presumably the DNA. It was anticipated that Auger electron emission, stimulated during the 157Gd (n, °)158Gd interaction, would impart additional high LET damage to that observed from the α-particle and Li ion during the 10B(n, α) 7Li reaction. Following irradiation with thermal neutrons from the Brookhaven Medical Research Reactor, the effectiveness of the Auger electrons was determined by comparing the response of cells incubated with 10BOPP, where damage was imparted by the boron neutron capture (BNC) products, to that from Gd-10BOP...

Photon activation therapy and brachytherapy

PURPOSE In photon activation therapy (PAT), energy deposition at critical sites within a tumor can be increased by complexing the DNA with higher Z atoms, and provoking the emission of Auger electrons after inducing a photoelectric effect. This in vivo study evaluates the hypothesis using X-rays from palladium-103 seeds to excite the L-edge of platinum (Pt) atoms bound to the DNA of cancerous cells. METHODS AND MATERIALS Pt (II) tetrakis(N-methyl-4-pyridyl) porphyrin chloride was used to locate Pt atoms adjacent to the DNA of the KHJJ murine mammary carcinoma; a 2.3-mCi palladium-103 seed was implanted in the tumor. RESULTS The tumor periphery received subtherapeutic doses. The rate of tumor growth in mice treated with PAT was slower than in mice treated with brachytherapy only. CONCLUSIONS The tumor growth delay for PAT-treated mice is attributed to Auger emission from Pt atoms that produced substantial local damage. However, other co-existing mechanisms cannot be ruled out.

In vivo studies in NCT with a boronated porphyrin and tumor growth delay as an end point

The robust carrying capacity of the porphyrin molecule and its propensity for localizing in tumor justified the synthesizing of a porphyrin labeled with boron for use in BNCT. However, problems associated with poor solubility impeded the utility of the molecule. Until BOPP was synthesized porphyrins were promising, but impractical. After in vitro experiments had demonstrated the biological efficacy of BOPP and had confirmed its intracellular localizing ability in vivo studies were carried out using mice. Irradiation of KHJJ murine mammary carcinoma to the TCD{sub 50} in a single fraction was precluded since this whole body dose is lethal. This problem was overcome by the use of radiation. BOPP was administered either as three 0.5 ml injections per day over two days or by continuous i.v. infusion, 2 ml per day over three days for a total dose of about 42 {mu}g {sup 10}B/gbw. Boron-10 distribution in the tumor at the time of irradiation was {approximately}20 {mu}g.

Analysis of 5-iodo-2′ -deoxyuridine incorporation in murine melanoma for photon activation therapy

Quantitative evaluation of the dose enhancement obtained with analog nucleoside agents such as iododeoxyuridine (IdUrd) requires knowledge of the degree to which the thymidine (Thd) in DNA is replaced by IdUrd. In the present investigation, mice were infused with IdUrd using an intravenous infusion apparatus capable of delivering continuous multi-day infusions without restraining the mice. The absolute incorporation of IdUrd in DNA was measured by 125IdUrd label, both in whole tissue and extracted DNA, showing a good correlation between levels observed in DNA and whole tissue. Replacement in a Harding-Passey murine melanoma tumor carried in BALB/c mice approached 10%. In addition, a Neutron Activation Analysis (NAA) technique was developed which showed in vitro, a sensitivity sufficient to evaluate the % replacement of Thd by IdUrd in small biological samples with a sensitivity greater than 0.1 ppm, at 1% replacement in mg samples. This method can provide information on iodine substitution in DNA in humans where the use of a radioactive DNA-seeking substance would be undesirable. Analyses of IdUrd incorporation in cultured cells by NAA and 125I counting showed good agreement.