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Perona M.,National Atomic Energy Commission CNEA | Rodriguez C.,National Atomic Energy Commission CNEA | Carpano M.,National Atomic Energy Commission CNEA | Thomasz L.,National Atomic Energy Commission CNEA | And 14 more authors.
Radiation and Environmental Biophysics

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 10BPA (10 μg 10B ml-1) + neutrons, or with 2, 4-bis (α,β-dihydroxyethyl)-deutero-porphyrin IX 10BOPP (10 μg10B 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) × 1010 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. © 2013 Springer-Verlag Berlin Heidelberg. Source

Molinari A.J.,Constituyentes Atomic Center | Pozzi E.C.C.,Constituyentes Atomic Center | Pozzi E.C.C.,Research and Production Reactors | Hughes A.M.,Constituyentes Atomic Center | And 13 more authors.
Radiation Research

In the present study the therapeutic effect and potential toxicity of the novel "“Sequential"†boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential"BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential"BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ±2% and 91 ±3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ±5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 ±12% and 60 ±22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential"BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue. © 2011 by Radiation Research Society. All rights of reproduction in any form reserved. Source

Aromando R.F.,University of Buenos Aires | Aromando R.F.,Constituyentes Atomic Center | Trivillin V.A.,Constituyentes Atomic Center | Heber E.M.,Constituyentes Atomic Center | And 5 more authors.
Oral Oncology

Mast cell (MC) activation in the hamster cheek pouch cancerization model is associated with the increase in tumor cell proliferation, mediated in turn by tryptase, a protease released from mast cell granules after activation. Tryptase induces tumor cell proliferation through the activation of PAR-2 (protease activated receptor-2) on the plasma membrane of carcinoma cells. The therapeutic success of boron neutron capture therapy mediated by boronophenylalanine (BPA-BNCT) in tumor control in the hamster cheek pouch oral cancer model has been previously reported by our laboratory. Early effects of BPA-BNCT on tumors of the hamster cheek pouch include a reduction in DNA-synthesis with the concomitant decrease in the proliferation of malignant cells. The aim of the present study was to investigate the early histological changes in mast cells after BPA-BNCT in tumors and premalignant tissue of the hamster cheek pouch. Tumor-bearing pouches were treated with BPA-BNCT or beam only (neutron irradiation without prior administration of the boron compound) and sacrificed 1 day after treatment. The samples were fixed in Carnoy fixative and stained with alcian blue-safranin to identify all the populations of mast cells. Total, active and inactive mast cells (MC) were counted in the connective tissue and the adventitious tissue underlying the pouch wall and at the base of the tumors in pouches treated with BPA-BNCT, in keeping with a previously described technique. BPA-BNCT induced a marked reduction in the total number of mast cells in the pouch (p < 0.05). This reduction in the total number of mast cells was due to a reduction in mast cells at the base of the tumor (p < 0.005) and it occurred at the expense of the active mast cells (p < 0.05). A slight reduction that did not reach statistical significance also occurred in the amount of mast cells in the pouch wall (that corresponds to the premalignant tissue in tumor-bearing pouches), and in the adventitious tissue. In this case the reduction was seen in the inactive population. Both BPA-BNCT and beam only elicited a qualitative change in the secretion modality of the granule content. Although further studies are needed to evaluate the subcellular effect of BNCT on mast cell granule secretion, the reduction in cell proliferation induced by BPA-BNCT would be partially due to the decrease in total mast cells in the hamster check pouch. © 2010 Elsevier Ltd. All rights reserved. Source

Heber E.M.,National University of Central Buenos Aires | Hughes A.M.,National University of Central Buenos Aires | Pozzi E.C.C.,National University of Central Buenos Aires | Pozzi E.C.C.,Research and Production Reactors | And 8 more authors.
Archives of Oral Biology

Objective: Given that locoregional recurrences developing from a tissue with potentially malignant disorders (PMD) in oral mucosa are a frequent cause of therapeutic failure, and that tissue with PMD is dose-limiting, the aim of the present study was to develop a model of tissue with PMD to evaluate the long-term therapeutic/toxic effects of different therapeutic modalities. Materials and methods: We evaluated 5 carcinogenesis protocols based on topical application of the carcinogen dimethyl-1,2-benzanthracene in the hamster cheek pouch, twice a week for 4, 6, 7, and 8 weeks and the classical 3 times a week for 12 weeks. Results: Long-term follow-up (8 months after protocol completion) was only possible with the 4- and 6-week carcinogenesis protocols. Tumour development increased progressively with time and aggressiveness of the carcinogenesis protocols. The time at which tumours developed in ≥90% of the animals was at protocol completion (T0) for the 12-week protocol, 1 month post-T0 for the 8-week protocol, 3 months post-T0 for the 7-week protocol and 4 months post-T0 for the 6-week protocol. <40% of the animals in the 4-week protocol developed tumours within the 8 months follow-up period. DNA synthesis rose as a function of time and protocol aggressiveness. Conclusions: The 6-week carcinogenesis protocol was selected for long-term studies of different therapeutic modalities in tissue with PMD because it permitted long-term follow-up and guaranteed tumour development in ≥90% of the animals. © 2009 Elsevier Ltd. Source

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