Improvement of the boron neutron capture therapy (BNCT) by the previous administration of the histone deacetylase inhibitor sodium butyrate for the treatment of thyroid carcinoma.

We have shown that boron neutron capture therapy (BNCT) could be an alternative for the treatment of poorly differentiated thyroid carcinoma (PDTC). Histone deacetylase inhibitors (HDACI) like sodium butyrate (NaB) cause hyperacetylation of histone proteins and show capacity to increase the gamma irradiation effect. The purpose of these studies was to investigate the use of the NaB as a radiosensitizer of the BNCT for PDTC. Follicular thyroid carcinoma cells (WRO) and rat thyroid epithelial cells (FRTL-5) were incubated with 1 mM NaB and then treated with boronophenylalanine ¹°BPA (10 µg ¹°B ml⁻¹) + neutrons, or with 2, 4-bis (α,ß-dihydroxyethyl)-deutero-porphyrin IX ¹°BOPP (10 µg ¹°B ml⁻¹) + neutrons, or with a neutron beam alone. The cells were irradiated in the thermal column facility of the RA-3 reactor (flux = (1.0 ± 0.1) × 10¹° n cm⁻² s⁻¹). Cell survival decreased as a function of the physical absorbed dose in both cell lines. Moreover, the addition of NaB decreased cell survival (p < 0.05) in WRO cells incubated with both boron compounds. NaB increased the percentage of necrotic and apoptotic cells in both BNCT groups (p < 0.05). An accumulation of cells in G2/M phase at 24 h was observed for all the irradiated groups and the addition of NaB increased this percentage. Biodistribution studies of BPA (350 mg kg⁻¹ body weight) 24 h after NaB injection were performed. The in vivo studies showed that NaB treatment increases the amount of boron in the tumor at 2-h post-BPA injection (p < 0.01). We conclude that NaB could be used as a radiosensitizer for the treatment of thyroid carcinoma by BNCT.

Qualitative autoradiography with polycarbonate foils enables histological and track analyses on the same section.

Neutron autoradiography is an imaging methodology that enables analysis of the spatial distribution of heavy ion emitters in a given material. In particular, it allows localization of (10)B in a tissue section put in contact with a nuclear track detector. Boron imaging is essential when considering boron neutron capture therapy as an option for treating cancerous tumors. A description of the autoradiography method is presented together with specific characteristics and technical details developed in our laboratory. We propose a new mounting technique to compare autoradiography images with the same section that gave rise to the latent tracks. The solid state nuclear track detector is polycarbonate, because it can be processed rapidly to obtain the autoradiographic results. It is a transparent material, which allows visualization of the sections mounted on it. Tissue can be removed easily and background is minimal.

In vitro studies of cellular response to DNA damage induced by boron neutron capture therapy.

The aim of these studies was to evaluate the mechanisms of cellular response to DNA damage induced by BNCT. Thyroid carcinoma cells were incubated with (10)BPA or (10)BOPP and irradiated with thermal neutrons. The surviving fraction, the cell cycle distribution and the expression of p53 and Ku70 were analyzed. Different cellular responses were observed for each irradiated group. The decrease of Ku70 in the neutrons +BOPP group could play a role in the increase of sensitization to radiation.

Studies for the application of boron neutron capture therapy to the treatment of differentiated thyroid cancer.

The aim of these studies was to evaluate the possibility of treating differentiated thyroid cancer by BNCT. These carcinomas are well controlled with surgery followed by therapy with (131)I; however, some patients do not respond to this treatment. BPA uptake was analyzed both in vitro and in nude mice implanted with cell lines of differentiated thyroid carcinoma. The boron intracellular concentration in the different cell lines and the biodistribution studies showed the selectivity of the BPA uptake by this kind of tumor.

Reference systems for the determination of 10B through autoradiography images: application to a melanoma experimental model.

The amount of (10)B in tissue samples may be determined by measuring the track density in the autoradiography image produced on a nuclear track detector. Different systems were evaluated as reference standards to be used for a quantitative evaluation of boron concentration. The obtained calibration curves were applied to evaluate the concentration of (10)B in melanoma tumour of NIH nude mice after a biodistribution study. The histological features observed in the tissue sections were accurately reproduced by the autoradiography images.

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.

The hamster cheek pouch as a model of oral cancer for boron neutron capture therapy studies: selective delivery of boron by boronophenylalanine.

Herein we propose and validate the hamster cheek pouch model of oral cancer for boron neutron capture therapy (BNCT) studies. This model serves to explore new applications of the technique, study the biology and radiobiology of BNCT, and assess the uptake of boron compounds and response of tumor, precancerous tissue, and clinically relevant normal tissues. These issues are central to evaluating and improving the therapeutic gain of BNCT. The success of BNCT is dependent on the absolute amount of boron in the tumor, and the tumor:blood and tumor:normal tissue boron concentration ratios. Within this context, biodistribution studies are pivotal. Tumors were induced in the hamsters with a carcinogenesis protocol that uses dimethyl-1,2-benzanthracene and mimics spontaneous tumor development in human oral mucosa. The animals were then used for biodistribution and pharmacokinetic studies of boronophenylalanine (BPA). Blood, tumor, precancerous pouch tissue surrounding tumor, normal pouch tissue, tongue, skin, cheek mucosa, palate mucosa, liver, and spleen, were sampled at 0-12 h after administration of 300 mg BPA/kg. The data reveal selective uptake of BPA by tumor tissue and, to a lesser degree, by precancerous tissue. Mean tumor boron concentration was 36.9 +/- 17.5 ppm at 3.5 h and the mean boron ratios were 2.4:1 for tumor:normal pouch tissue and 3.2:1 for tumor:blood. Higher doses of BPA (600 and 1200 mg BPA/kg) increased tumor uptake. Potentially therapeutic absolute boron concentrations, and tumor:normal tissue and tumor:blood ratios can be achieved in the hamster oral cancer model using BPA as the delivery agent.