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Purpose: Boron neutron capture therapy (BNCT) combines selective accumulation of 10B carriers in tumor tissue with subsequent neutron irradiation. BNCT has been proposed for the treatment of multiple, non-resectable, diffuse tumors in lung. The aim of the present study was to evaluate the therapeutic efficacy and toxicity of BNCT in an experimental model of lung metastases of colon carcinoma in BDIX rats and perform complementary survival studies. Materials and methods: We evaluated tumor control and toxicity in lung 2 weeks post-BNCT at 2 dose levels, including 5 experimental groups per dose level: T0 (euthanized pre-treatment), Boronophenylalanine-BNCT (BPA-BNCT), BPA + Sodium decahydrodecaborate-BNCT ((BPA + GB-10)-BNCT), Beam only (BO) and Sham (no treatment, same manipulation). Tumor response was assessed employing macroscopic and microscopic end-points. An additional experiment was performed to evaluate survival and oxygen saturation in blood. Results and conclusions: No dose-limiting signs of short/medium-term toxicity were observed in lung. All end-points revealed statistically significant BNCT-induced tumor control vs Sham at both dose levels. The survival experiment showed a statistically significant 45% increase in post-treatment survival time in the BNCT group (48 days) versus Sham (33 days). These data consistently revealed growth suppression of lung metastases by BNCT with no manifest lung toxicity. Boron Neutron Capture Therapy suppresses growth of experimental lung metastases No BNCT-induced short/medium-term toxicity in lung is associated with tumor control Boron Neutron Capture Therapy increased post-treatment survival time by 45% [ABSTRACT FROM AUTHOR]

We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer. Blood vessel normalization was induced by two doses of thalidomide in tumor-bearing hamsters on 2 consecutive days. All studies in thalidomide-treated animals were performed 48 h after the first dose of thalidomide, previously established as the window of normalization. Biodistribution studies were performed with BPA at a dose of 15.5 mg 10B/kg in thalidomide-treated (Th++) and untreated (Th-) tumor-bearing hamsters. The effect of blood vessel normalization prior to BPA administration on the efficacy of BNCT was assessed in in vivo BNCT studies at the RA-3 Nuclear Reactor in tumor-bearing hamsters. Group I was treated with BPA-BNCT after treatment with thalidomide (Th++ BPA-BNCT). Group II was treated with BPA-BNCT alone (Th- BPA-BNCT). Group III was treated with the beam only after treatment with thalidomide (Th++ BO), and Group IV was treated with the beam only (Th- BO). Groups I and II were given the same dose of BPA (15.5 mg 10B/kg), and all groups (I-IV) were exposed to the same neutron fluence. Two additional groups were treated with the beam only at a higher dose to exacerbate mucositis in precancerous tissue and to explore the potential direct protective effect of thalidomide on radiation-induced mucositis in a scenario of more severe toxicity, i.e. Group V (Th++ hdBO) and Group VI (Th- hdBO). The animals were followed for 28 days. Biodistribution studies revealed no statistically significant differences in gross boron content between Th++ and Th- animals. Overall tumor control (complete response ++ partial response) at 28 days post-treatment was significantly higher for Group I (Th++ BPA-BNCT) than for Group II (Th- BPA-BNCT): 84 ± 3%% compared to 67 ± 5%%. Pretreatment with thalidomide did not induce statistically significant changes in overall tumor control induced by the beam only, i.e. 15 ± 5%% in Group III (Th++ BO) and 18 ± 5%% in Group IV (Th- BO), or in overall tumor control induced by the high-dose beam only, i.e. 60 ± 7%% in Group V (Th++ hdBO) and 47 ± 10%% in Group VI (Th- hdBO). BPA-BNCT alone (Group II) induced mucositis in precancerous tissue that reached Grades 3-4 in 80%% of the animals, whereas pretreatment with thalidomide (Group I) prevented mucositis Grades 3 and 4 completely. Beam-only Group III (Th++ BO) exhibited only Grade 1 mucositis in precancerous tissue, whereas 17%% of the animals in beam-only Group IV (Th- BO) reached Grade 2 mucositis. High-dose beam-only group V (Th++ hdBO) exhibited only Grade 2 mucositis, whereas high-dose beam-only group VI (Th- hdBO) reached Grade 3 mucositis in 83%% of the animals. In all cases mucositis in precancerous tissue was reversible. No normal tissue radiotoxicity was observed with any of the protocols. Pretreatment with thalidomide enhanced the therapeutic efficacy of BNCT and reduced precancerous tissue toxicity. [ABSTRACT FROM AUTHOR]

Summary: 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 1day 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. [Copyright &y& Elsevier]

Abstract: Objective: We previously reported the therapeutic success of different BNCT protocols in the treatment of oral cancer, employing the hamster cheek pouch model. The aim of the present study was to evaluate the effect of these BNCT protocols on DNA synthesis in precancerous and normal tissue in this model and assess the potential lag in the development of second primary tumors in precancerous tissue. The data are relevant to potential control of field cancerized tissue and tolerance of normal tissue. Materials and methods: We evaluated DNA synthesis in precancerous and normal pouch tissue 1–30 days post-BNCT mediated by boronophenylalanine (BPA), GB-10 (Na2 10B10H10) or (BPA+GB-10) employing incorporation of 5-bromo-2′-deoxyuridine as an end-point. The BNCT-induced potential lag in the development of second primary tumors from precancerous tissue was monitored. Results: A drastic, statistically significant reduction in DNA synthesis occurred in precancerous tissue as early as 1 day post-BNCT and was sustained at virtually all time-points until 30 days post-BNCT for all the protocols. The histological categories evaluated individually within precancerous tissue (dysplasia, hyperplasia and NUMF [no unusual microscopic features]) responded similarly. DNA synthesis in normal tissue treated with BNCT oscillated around the very low pre-treatment values. A BNCT-induced lag in the development of second primary tumors was observed. Conclusions: BNCT induced a drastic fall in DNA synthesis in precancerous tissue that would be associated to the observed lag in the development of second primary tumors. The minimum variations in DNA synthesis in BNCT-treated normal tissue would correlate with the absence of normal tissue radiotoxicity. The present data would support the control of field-cancerized areas by BNCT. [Copyright &y& Elsevier]

Summary: Given the clinical relevance of locoregional recurrences in head and neck cancer, we developed a novel experimental model of premalignant tissue in the hamster cheek pouch for long-term studies and demonstrated the partial inhibitory effect of a single application of Boron Neutron Capture Therapy (BNCT) on tumor development from premalignant tissue. The aim of the present study was to evaluate the effect of a double application of BNCT with a 6week interval in terms of inhibitory effect on tumor development, toxicity and DNA synthesis. We performed a double application, 6weeks apart, of (1) BNCT mediated by boronophenylalanine (BPA-BNCT); (2) BNCT mediated by the combined application of decahydrodecaborate (GB-10) and BPA [(GB-10+BPA)-BNCT] or (3) beam-only, at RA-3 nuclear reactor and followed the animals for 8months. The control group was cancerized and sham-irradiated. BPA-BNCT, (GB-10+BPA)-BNCT and beam-only induced a reduction in tumor development from premalignant tissue that persisted until 8, 3, and 2months respectively. An early maximum inhibition of 100% was observed for all 3 protocols. No normal tissue radiotoxicity was detected. Reversible mucositis was observed in premalignant tissue, peaking at 1week and resolving by the third week after each irradiation. Mucositis after the second application was not exacerbated by the first application. DNA synthesis was significantly reduced in premalignant tissue 8months post-BNCT. A double application of BPA-BNCT and (GB-10+BPA)-BNCT, 6weeks apart, could be used therapeutically at no additional cost in terms of radiotoxicity in normal and dose-limiting tissues. [Copyright &y& Elsevier]