Effect Of Neutron Capture Therapy Research Articles

Image-Guided Neutron Capture Therapy Using the Gd-DO3A-BTA Complex as a New Combinatorial Treatment Approach.

Gadolinium-neutron capture therapy (Gd-NCT) is based on the nuclear capture reaction that occurs when 157Gd is irradiated with low energy thermal neutrons to primarily produce gamma photons. Herein, we investigated the effect of neutron capture therapy (NCT) using a small molecular gadolinium complex, Gd-DO3A-benzothiazole (Gd-DO3A-BTA), which could be a good candidate for use as an NCT drug due to its ability to enter the intracellular nuclei of tumor cells. Furthermore, MRI images of Gd-DO3A-BTA showed a clear signal enhancement in the tumor, and the images also played a key role in planning NCT by providing accurate information on the in vivo uptake time and duration of Gd-DO3A-BTA. We injected Gd-DO3A-BTA into MDA-MB-231 breast tumor-bearing mice and irradiated the tumors with cyclotron neutrons at the maximum accumulation time (postinjection 6 h); then, we observed the size of the growing tumor for 60 days. Gd-DO3A-BTA showed good therapeutic effects of chemo-Gd-NCT for the in vivo tumor models. Simultaneously, the Gd-DO3A-BTA groups ([Gd-DO3A-BTA(+), NCT(+)]) showed a significant reduction in tumor size (p < 0.05), and the inhibitory effect on tumor growth was exhibited in the following order: [Gd-DO3A-BTA(+), NCT(+)] > [Gd-DO3A-BTA(+), NCT(−)] > [Gd-DO3A-BTA(−), NCT(+)] > [Gd-DO3A-BTA(−), NCT(−)]. On day 60, the [Gd-DO3A-BTA(+), NCT(+)] and [Gd-DO3A-BTA(−), NCT(−)] groups exhibited an approximately 4.5-fold difference in tumor size. Immunohistochemistry studies demonstrated that new combinational therapy with chemo-Gd-NCT could treat breast cancer by both the inhibition of tumor cell proliferation and induction of apoptosis-related proteins, with in vivo tumor monitoring by MRI.

Effect of neutron capture therapy on the cell cycle of human squamous cell carcinoma cells

Purpose: The effects of boronophenylalanine (BPA)-mediated boron neutron capture therapy (BNCT) on the growth potential and cell cycle of human oral squamous cell carcinoma (SCC) cells were examined.Materials and methods: SAS cells expressing a functional wild-type p53 were exposed to neutron beams in the presence of BPA and growth potential was measured by colony formation assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell cycle and cell cycle-related proteins were examined by flow cytometry and immunoblot analysis.Results: BNCT affected the colony-forming ability and viability of SAS cells. In the flow-cytometric analysis of BNCT-treated cells, the cell cycle was arrested at the G1 and G2 checkpoints, and sub-G1 cells appeared. Apoptotic cells were detected by nuclear DNA staining. Immunoblot analysis revealed the phosphorylation of p53, up-regulation of p21, and down-regulation of retinoblastoma (Rb) gene protein at 6 h after BNCT. Twelve hours after BNCT, the up-regulation of Wee1, phosphorylation of cdc2, and up-regulation of cyclin B1 were observed. Cleavage of poly (ADP-ribose) polymerase (PARP) occurred from 6 h after BNCT.Conclusion: These results indicate that the early inhibitory effect of BNCT on the growth of human oral SCC cells can be ascribed to arrest at the G1 and G2 checkpoints and apoptosis associated with G1 arrest.

Electroporation increases the effect of borocaptate ( 10B-BSH) in neutron capture therapy

Purpose: The cell membrane permeability of borocaptate ( 10B-BSH) and its extent of accumulation in cells are controversial. This study was performed to elucidate these points. Methods and Materials: Two different treatments were applied to SCCVII tumor cells. The first group of tumor cells was incubated in culture medium with 10B-BSH or 10B-enriched boric acid, and was exposed to neutrons from the heavy water facility of the Kyoto University Reactor (KUR). More than 99% of neutrons were thermal neutrons at flux base. The second group was pretreated by electroporation in combination with 10B-BSH, and thereafter the cells were irradiated with neutrons. The cell killing effects of boron neutron capture therapy (BNCT) using BSH were investigated by colony formation assay. Results: Surviving cell fraction decreased exponentially with neutron fluence, and addition of BSH significantly enhanced the cell killing effect of neutron capture therapy (NCT) depending on 10B concentration. The effect of BSH-BNCT also increased with preincubation time of cells in the medium containing BSH. The electroporation of cells with BSH at 10 ppm 10B markedly enhanced BSH-BNCT effects in comparison with that of preincubation alone. The effect of BSH-BNCT with electroporation was equal to that of BNCT using 10B-boric acid at a same 10B concentration (10 ppm). Conclusions: BSH is suggested to penetrate the cells slowly and remained after washing. Electroporation can introduce BSH into the cells very efficiently, and BSH stays in the cells and is not lost by washing. Therefore, if electroporation is applied to tumors after BSH injection, 10B remains in tumors but is cleared from normal tissues, and selective accumulation of 10B in tumors will be achieved after an adequate waiting time.

Neutron capture therapy with gadopentetate dimeglumine: Experiments on tumor-bearing rats

The therapeutic effect of neutron capture therapy with the gadolinium (Gd) complex gadopentetate dimeglumine was studied in vivo in rats using a beam of thermal neutrons. Rats with Jensen sarcomas 10-15 mm in diameter in their right thigh were irradiated with a thermal neutron beam that had fluences of 3.6 x 10(11) (20 min) or 5.4 x 10(11) n/cm2 (30 min) in the absence and presence of 5,500 or 13,750 ppm gadopentetate dimeglumine. Gadopentetate dimeglumine was administered directly into the tumor prior to neutron irradiation. Four groups of rats were studied: two groups of nonirradiated controls (Gd-n- and Gd+n-) and two irradiated groups (Gd-n+ and Gd+n+). In the follow-up period, we measured the subjects' clinical status and tumor size as a function of time postirradiation. In both control groups (Gd-n- and Gd+n-), the tumor progressively grew. Pure irradiation by thermal neutrons in the Gd-n+ group resulted in a transient inhibition of tumor growth with total regressions of 15%. Intratumoral administration of 13,750 ppm gadolinium per gram of tumor and subsequent neutron irradiation (the Gd+n+ group; fluence = 3.6.10(11) n/cm2) significantly increased the tumoricidal effects (i.e., decrease of tumor growth up to a complete regression of the tumors in about 80%). Treatment-specific differences between the groups were confirmed by histologic observations. The intratumoral administration of the hydrophilic magnetic resonance imaging contrast medium gadopentetate dimeglumine prior to irradiation with thermal neutrons leads to a therapeutic gain (i.e., reduction) on experimental Jensen sarcomas.

Intracellular distribution of various boron compounds for use in boron neutron capture therapy

The neutron capture reaction in boron ( 10B(n,α) 7Li) generates two short-range particles with high linear energy transfer. The effect of neutron capture therapy depends on the selective localization of 10B atoms in target cells. The determination of the distribution of boron compounds in cancer cells at the subcellular level is required for the understanding of the effect of this treatment. The monomeric sulfhydryl borane (BSH) compound has been used clinically in Japan and preclinically in the U.S.A. Recently, new compounds have been developed: a dimeric sulfhydryl borane (BSSB), a boronophenylalanine (BPA), and two porphyrin complexes (BOPP and VCDP). This study demonstrates that the porphyrin complexes (BOPP and VCDP) are more cytotoxic than the other three compounds to the rat 9L gliosarcoma cell line. Using atomic absorption spectrophotometry to determine boron content for cellular uptake studies of these agents, we found that of the five compounds tested BOPP (25 μM) exposure resulted in the greatest boron uptake averaging 305 ng B/10 6 cells. BSSB (500 μM) was second averaging 93 ng B/10 6 cells, BSH (500 μM) third averaging 62 ng B/10 6 cells, VCDP (25 μM) fourth averaging 58 ng B/10 6 cells, and BPA (500 μM) fifth averaging 7.4 ng B/10 6 cells. Data on the distribution of boron in the nuclei, mitochondria, lysosomes, microsomes, and cytosomes of 9L cells are also presented.

Epithermal Neutron Beam Design for Neutron Capture Therapy at the Power Burst Facility and the Brookhaven Medical Research Reactor

Nuclear design studies have been performed for two reactor-based epithermal neutron beams for cancer treatment by neutron capture therapy (NCT). An intermediate-intensity epithermal beam has been designed and implemented at the Brookhaven Medical Research Reactor (BMRR). Measurements show that the BMRR design predictions for the principal characteristics of this beam are accurate. A canine program for research into the biological effects of NCT is now under way at BMRR. The design for a high-intensity epithermal beam with minimal contamination from undesirable radiation components has been finalized for the Power Burst Facility (PBF) at the Idaho National Engineering Laboratory. This design will be implemented when it is determined that human NCT trials are advisable. The PBF beam will exhibit approximately an order of magnitude improvement in absolute epithermal flux intensity over that available in the BMRR, and its angular distribution and spectral characteristics will be more advantageous for NCT. The combined effects of beam intensity, angular distribution, spectrum, and contaminant level allow the desired tumor radiation dose to be delivered in much shorter times than are possible with the currently available BMRR beam, with a significant reduction (factor of 3 to 5) in collateral dose due to beam contaminants.

Long range effects of neutron capture therapy of cancer in mice II. Dose effect

An index is established which compares the outcome of neutron therapy experiments when only a single exposure is given to a transplantable malignant neoplasm in mice if the thermal neutron attenuation in passing through the tumor and tumor boron concentration at the time of exposure are known. A high degree of correlation is shown for the EXIT RAD INDEX in tables and graphs recording and summarizing studies done on some 3500 mice treated for thigh-implanted malignant neoplasms varying from 8–17 mm in dia. at treatment time. The end point was permanent, total regression of the neoplasm occurring without scarring Each animal with a treated neoplasm was followed until death. It is shown that this INDEX makes possible valid comparisons of procedures carried out over several years and in which exposure times vary from 0.1 sec to 23 min in three different reactors at two different boron dosages.

Long range effects of neutron capture therapy of cancer in mice—I Correlation between the time of intracellular residence of 10BNapentaborate and the regression of the tumor

In 1587 mice, each bearing a potentially lethal neoplasm implanted in the right thigh, the tumoricidal effects of a single exposure to a standard thermal neutron fluence, ranging from 1.41 to 1.67 x 10 12/cm 2, following an intravenous injection of sodium pentaborate of 35 ug l0B/g observed body weight were observed. Observations were continued for the lifetime of the animal. Regression, measured by tumor diameter, began in every instance within a maximum of four days after treatment. After two weeks clear evidence of tumor growth resumption was apparent in some animals; however, in a majority, the disappearance of the tumor was complete and permanent. For each size of neoplasm studied, the percentage of tumor which permanently regressed rose to a maximum with increased residence time of boron in the tumor and then fell. The rise and fall of neoplasm regression do not parallel observed data on tumor borate concentration over the time-intervals observed. In neoplasms 8 mm dia., permanent regression occurred in 93% of the neoplasms when the borate intracellular-residence interval in the neoplasm was 7–11 min, fell to 74% in the 50 min residence interval and to 42% in the 88 min residence period. In neoplasms 9–11 mm dia., regression was 58% in the 7–11 min interval, rose to 86% in the 38–48 min period and thereafter fell to 19% in the 88–92 min residence interval. In animals with neoplasms 12–14 mm dia., regression was 22% in the 7–11 min interval, rose to 38% in the 50–60 min interval and fell to zero in the 74–80 min interval. The possible cellular mechanisms provoked by the reaction and their relationship to a calculated dose formulated on neutron fluence and boron-10 concentration will be explored in a subsequent communication.