RESUMO
OBJECTIVE(S): The hamster carcinogenesis model recapitulates oral oncogenesis. Dimethylbenz[a]anthracene (DMBA) cancerization induces early severe mucositis, affecting animal's welfare and causing tissue loss and pouch shortening. "Short" pouches cannot be everted for local irradiation for boron neutron capture therapy (BNCT). Our aim was to optimize the DMBA classical cancerization protocol to avoid severe mucositis, without affecting tumor development. We evaluated BNCT in animals cancerized with this novel protocol. MATERIALS AND METHODS: We studied: Classical cancerization protocol (24 applications) and Classical with two interruptions (completed at the end of the cancerization protocol). BNCT mediated by boronophenylalanine (BPA) was performed in both groups. RESULTS: The twice-interrupted group exhibited a significantly lower percentage of animals with severe mucositis versus the non-interrupted group (17% versus 71%) and a significantly higher incidence of long pouches (100% versus 53%). Tumor development and the histologic characteristics of tumor and precancerous tissue were not affected by the interruptions. For both groups, overall tumor response was more than 80%, with a similar incidence of BNCT-induced severe mucositis. CONCLUSION(S): The twice-interrupted protocol reduced severe mucositis during cancerization without affecting tumor development. This favored the animal's welfare and reduced the number of animals to be cancerized for our studies, without affecting BNCT response.
RESUMO
Boron neutron capture therapy (BNCT) is a promising cancer binary therapy modality that utilizes the nuclear capture reaction of thermal neutrons by boron-10 resulting in a localized release of high- and low-linear energy transfer (LET) radiation. Electrochemotherapy (ECT) is based on electroporation (EP) that induces opening of pores in cell membranes, allowing the entry of compounds. Because EP is applied locally to a tumor, the compound is incorporated preferentially by tumor cells. Based on the knowledge that the therapeutic success of BNCT depends centrally on the boron content in tumor and normal tissues and that EP has proven to be an excellent facilitator of tumor biodistribution of an anti-tumor agent, the aim of this study was to evaluate if EP can optimize the delivery of boronated compounds. We performed biodistribution studies and qualitative microdistribution analyses of boron employing the boron compound sodium decahydrodecaborate (GB-10) + EP in the hamster cheek pouch oral cancer model. Syrian hamsters with chemically induced exophytic squamous cell carcinomas were used. A typical EP treatment was applied to each tumor, varying the moment of application with respect to the administration of GB-10 (early or late). The results of this study showed a significant increase in the absolute and relative tumor boron concentration and optimization of the qualitative microdistribution of boron by the use of early EP + GB-10 versus GB-10 without EP. This strategy could be a tool to improve the therapeutic efficacy of BNCT/GB-10 in vivo.
Assuntos
Compostos de Boro/metabolismo , Terapia por Captura de Nêutron de Boro/métodos , Boro/metabolismo , Isótopos/metabolismo , Animais , Bochecha , Cricetinae , Modelos Animais de Doenças , Mesocricetus , Neoplasias Bucais , Distribuição TecidualRESUMO
Boron neutron capture therapy (BNCT) is based on selective accumulation of B-10 carriers in tumor followed by neutron irradiation. We demonstrated, in 2001, the therapeutic effect of BNCT mediated by BPA (boronophenylalanine) in the hamster cheek pouch model of oral cancer, at the RA-6 nuclear reactor. Between 2007 and 2011, the RA-6 was upgraded, leading to an improvement in the performance of the BNCT beam (B2 configuration). Our aim was to evaluate BPA-BNCT radiotoxicity and tumor control in the hamster cheek pouch model of oral cancer at the new "B2" configuration. We also evaluated, for the first time in the oral cancer model, the radioprotective effect of histamine against mucositis in precancerous tissue as the dose-limiting tissue. Cancerized pouches were exposed to: BPA-BNCT; BPA-BNCT + histamine; BO: Beam only; BO + histamine; CONTROL: cancerized, no-treatment. BNCT induced severe mucositis, with an incidence that was slightly higher than in "B1" experiments (86 vs 67%, respectively). BO induced low/moderate mucositis. Histamine slightly reduced the incidence of severe mucositis induced by BPA-BNCT (75 vs 86%) and prevented mucositis altogether in BO animals. Tumor overall response was significantly higher in BNCT (94-96%) than in control (16%) and BO groups (9-38%), and did not differ significantly from the "B1" results (91%). Histamine did not compromise BNCT therapeutic efficacy. BNCT radiotoxicity and therapeutic effect at the B1 and B2 configurations of RA-6 were consistent. Histamine slightly reduced mucositis in precancerous tissue even in this overly aggressive oral cancer model, without compromising tumor control.
Assuntos
Terapia por Captura de Nêutron de Boro/efeitos adversos , Terapia por Captura de Nêutron de Boro/instrumentação , Bochecha , Neoplasias Bucais/etiologia , Neoplasias Induzidas por Radiação/etiologia , Reatores Nucleares , Pesquisa Translacional Biomédica , Animais , Cricetinae , Modelos Animais de Doenças , Histamina/farmacologia , Neoplasias Bucais/prevenção & controle , Neoplasias Induzidas por Radiação/prevenção & controle , Protetores contra Radiação/farmacologiaRESUMO
The aim of the present study was to evaluate, for the first time, the abscopal effect of boron neutron capture therapy (BNCT). Twenty-six BDIX rats were inoculated subcutaneously with 1 × 106 DHD/K12/TRb syngeneic colon cancer cells in the right hind flank. Three weeks post-inoculation, the right leg of 12 rats bearing the tumor nodule was treated with BPA-BNCT (BPA-Boronophenylalanine) at the RA-3 nuclear reactor located in Buenos Aires, Argentina, at an absorbed dose of 7.5 Gy to skin as the dose-limiting tissue. The remaining group of 14 tumor-bearing rats were left untreated and used as control. Two weeks post-BNCT, 1 × 106 DHD/K12/TRb cells were injected subcutaneously in the contralateral left hind flank of each of the 26 BDIX rats. Tumor volume in both legs was measured weekly for 7 weeks to determine response to BNCT in the right leg and to assess a potential influence of BNCT in the right leg on tumor development in the left leg. Within the BNCT group, a statistically significant reduction was observed in contralateral left tumor volume in animals whose right leg tumor responded to BNCT (post-treatment/pre-treatment tumor volume <1) versus animals who failed to respond (post/pre ≥1), i.e., 13 ± 15 vs 271 ± 128 mm3. In addition, a statistically significant reduction in contralateral left leg tumor volume was observed in BNCT-responsive animals (post/pre <1) vs untreated animals, i.e., 13 ± 15 vs 254 ± 251 mm3. The present study performed in a simple animal model provides proof of principle that the positive response of a tumor to BNCT is capable of inducing an abscopal effect.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias do Colo/radioterapia , Animais , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Imunoterapia , Masculino , Metástase Neoplásica , RatosRESUMO
The application of boron neutron capture therapy (BNCT) mediated by liposomes containing (10)B-enriched polyhedral borane and carborane derivatives for the treatment of head and neck cancer in the hamster cheek pouch oral cancer model is presented. These liposomes are composed of an equimolar ratio of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH3(CH2)15-7,8-C2B9H11] (MAC) in the bilayer membrane while encapsulating the hydrophilic species Na3[ae-B20H17NH3] (TAC) in the aqueous core. Unilamellar liposomes with a mean diameter of 83 nm were administered i.v. in hamsters. After 48 h, the boron concentration in tumors was 67 ± 16 ppm whereas the precancerous tissue contained 11 ± 6 ppm, and the tumor/normal pouch tissue boron concentration ratio was 10:1. Neutron irradiation giving a 5-Gy dose to precancerous tissue (corresponding to 21 Gy in tumor) resulted in an overall tumor response (OR) of 70% after a 4-wk posttreatment period. In contrast, the beam-only protocol gave an OR rate of only 28%. Once-repeated BNCT treatment with readministration of liposomes at an interval of 4, 6, or 8 wk resulted in OR rates of 70-88%, of which the complete response ranged from 37% to 52%. Because of the good therapeutic outcome, it was possible to extend the follow-up of BNCT treatment groups to 16 wk after the first treatment. No radiotoxicity to normal tissue was observed. A salient advantage of these liposomes was that only mild mucositis was observed in dose-limiting precancerous tissue with a sustained tumor response of 70-88%.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro/farmacologia , Neoplasias Bucais/radioterapia , Neoplasias Experimentais/radioterapia , Animais , Boro/efeitos adversos , Terapia por Captura de Nêutron de Boro/efeitos adversos , Cricetinae , Ensaios de Seleção de Medicamentos Antitumorais , Lipossomos , Mesocricetus , Neoplasias Bucais/patologia , Neoplasias Experimentais/patologia , Fatores de TempoRESUMO
Rheumatoid arthritis is a chronic autoimmune pathology characterized by the proliferation and inflammation of the synovium. Boron neutron capture synovectomy (BNCS), a binary treatment modality that combines the preferential incorporation of boron carriers to target tissue and neutron irradiation, was proposed to treat the pathological synovium in arthritis. In a previous biodistribution study, we showed the incorporation of therapeutically useful boron concentrations to the pathological synovium in a model of antigen-induced arthritis (AIA) in rabbits, employing two boron compounds approved for their use in humans, i.e., decahydrodecaborate (GB-10) and boronophenylalanine (BPA). The aim of the present study was to perform low-dose BNCS studies at the RA-1 Nuclear Reactor in the same model. Neutron irradiation was performed post intra-articular administration of BPA or GB-10 to deliver 2.4 or 3.9 Gy, respectively, to synovium (BNCS-AIA). AIA and healthy animals (no AIA) were used as controls. The animals were followed clinically for 2 months. At that time, biochemical, magnetic resonance imaging (MRI) and histological studies were performed. BNCS-AIA animals did not show any toxic effects, swelling or pain on palpation. In BNCS-AIA, the post-treatment levels of TNF-α decreased in four of six rabbits and IFN-γ levels decreased in five of six rabbits. In all cases, MRI images of the knee joint in BNCS-AIA resembled those of no AIA, with no necrosis or periarticular effusion. Synovial membranes of BNCS-AIA were histologically similar to no AIA. BPA-BNCS and GB-10-BNCS, even at low doses, would be therapeutically useful for the local treatment of rheumatoid arthritis.
Assuntos
Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/radioterapia , Terapia por Captura de Nêutron de Boro/instrumentação , Ovalbumina/farmacologia , Sinovectomia , Animais , Terapia por Captura de Nêutron de Boro/efeitos adversos , Modelos Animais de Doenças , Feminino , Coelhos , Radiobiologia , Dosagem Radioterapêutica , Segurança , Membrana Sinovial/efeitos da radiaçãoRESUMO
BACKGROUND: We previously demonstrated the therapeutic success of sequential boron neutron capture therapy (Seq-BNCT) in the hamster cheek pouch oral cancer model. It consists of BPA-BNCT followed by GB-10-BNCT 24 or 48 hours later. Additionally, we proved that tumor blood vessel normalization with thalidomide prior to BPA-BNCT improves tumor control. The aim of the present study was to evaluate the therapeutic efficacy and explore potential boron microdistribution changes in Seq-BNCT preceded by tumor blood vessel normalization. MATERIAL AND METHODS: Tumor bearing animals were treated with thalidomide for tumor blood vessel normalization, followed by Seq-BNCT (Th+ Seq-BNCT) or Seq-Beam Only (Th+ Seq-BO) in the window of normalization. Boron microdistribution was assessed by neutron autoradiography. RESULTS: Th+ Seq-BNCT induced overall tumor response of 100%, with 87 (4)% complete tumor response. No cases of severe mucositis in dose-limiting precancerous tissue were observed. Differences in boron homogeneity between tumors pre-treated and not pre-treated with thalidomide were observed. CONCLUSION: Th+ Seq-BNCT achieved, for the first time, response in all treated tumors. Increased homogeneity in tumor boron microdistribution is associated to an improvement in tumor control.
Assuntos
Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Bucais/radioterapia , Neovascularização Patológica/tratamento farmacológico , Fenilalanina/análogos & derivados , 9,10-Dimetil-1,2-benzantraceno , Inibidores da Angiogênese/uso terapêutico , Animais , Compostos de Boro/farmacocinética , Carcinógenos , Cricetinae , Mesocricetus , Neoplasias Bucais/irrigação sanguínea , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/metabolismo , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Lesões Pré-Cancerosas/irrigação sanguínea , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/radioterapia , Talidomida/uso terapêuticoRESUMO
Boron neutron capture synovectomy (BNCS) is explored for the treatment of rheumatoid arthritis (RA). The aim of the present study was to perform boron biodistribution studies in a model of antigen-induced arthritis (AIA) in female New Zealand rabbits, with the boron carriers boronophenylalanine (BPA) and sodium decahydrodecaborate (GB-10) to assess the potential feasibility of BNCS for RA. Rabbits in chronic phase of AIA were used for biodistribution studies employing the following protocols: intra-articular (ia) (a) BPA-f 0.14 M (0.7 mg (10)B), (b) GB-10 (5 mg (10)B), (c) GB-10 (50 mg (10)B) and intravenous (iv), (d) BPA-f 0.14 M (15.5 mg (10)B/kg), (e) GB-10 (50 mg (10)B/kg), and (f) BPA-f (15.5 mg (10)B/kg) + GB-10 (50 mg (10)B/kg). At different post-administration times (13-85 min for ia and 3 h for iv), samples of blood, pathological synovium (target tissue), cartilage, tendon, muscle, and skin were taken for boron measurement by inductively coupled plasma mass spectrometry. The intra-articular administration protocols at <40 min post-administration both for BPA-f and GB-10, and intravenous administration protocols for GB-10 and [GB-10 + BPA-f] exhibited therapeutically useful boron concentrations (>20 ppm) in the pathological synovium. Dosimetric estimations suggest that BNCS would be able to achieve a therapeutically useful dose in pathological synovium without exceeding the radiotolerance of normal tissues in the treatment volume, employing boron carriers approved for use in humans. Radiobiological in vivo studies will be necessary to determine the actual therapeutic efficacy of BNCS to treat RA in an experimental model.
Assuntos
Antígenos/efeitos adversos , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/terapia , Terapia por Captura de Nêutron de Boro , Boro/farmacocinética , Boro/uso terapêutico , Animais , Compostos de Boro/farmacocinética , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Frutose/análogos & derivados , Frutose/farmacocinética , Coelhos , Distribuição TecidualRESUMO
Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. Employing an experimental model of liver metastases in rats, we recently demonstrated that BNCT mediated by boronophenylalanine (BPA-BNCT) at 13 Gy prescribed to tumor is therapeutically useful at 3-week follow-up. The aim of the present study was to evaluate doseresponse at 5-week follow-up, based on retrospective dose assessment in individual rats. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA-BNCT (n = 19), Beam only (n = 8) and Sham (n = 7) (matched manipulation, no treatment). For each rat, neutron flux was measured in situ and boron content was measured in a pre-irradiation blood sample for retrospective individual dose assessment. For statistical analysis (ANOVA), individual data for the BPA-BNCT group were pooled according to absorbed tumor dose, BPA-BNCT I: 4.58.9 Gy and BPA-BNCT II: 9.216 Gy. At 5 weeks post-irradiation, the tumor surface area post-treatment/pre-treatment ratio was 12.2 ± 6.6 for Sham, 7.8 ± 4.1 for Beam only, 4.4 ± 5.6 for BPA-BNCT I and 0.45 ± 0.20 for BPA-BNCT II; tumor nodule weight was 750 ± 480 mg for Sham, 960 ± 620 mg for Beam only, 380 ± 720 mg for BPA-BNCT I and 7.3 ± 5.9 mg for BPA-BNCT II. The BPA-BNCT II group exhibited statistically significant tumor control with no contributory liver toxicity. Potential threshold doses for tumor response and significant tumor control were established at 6.1 and 9.2 Gy, respectively.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Animais , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Masculino , Dosagem Radioterapêutica , Ratos , Estudos RetrospectivosRESUMO
Boron neutron capture therapy (BNCT) is based on selective accumulation of ¹°B carriers in tumor followed by neutron irradiation. We previously proved the therapeutic success of BNCT mediated by the boron compounds boronophenylalanine and sodium decahydrodecaborate (GB-10) in the hamster cheek pouch oral cancer model. Based on the clinical relevance of the boron carrier sodium borocaptate (BSH) and the knowledge that the most effective way to optimize BNCT is to improve tumor boron targeting, the specific aim of this study was to perform biodistribution studies of BSH in the hamster cheek pouch oral cancer model and evaluate the feasibility of BNCT mediated by BSH at nuclear reactor RA-3. The general aim of these studies is to contribute to the knowledge of BNCT radiobiology and optimize BNCT for head and neck cancer. Sodium borocaptate (50 mg ¹°B/kg) was administered to tumor-bearing hamsters. Groups of 3-5 animals were killed humanely at nine time-points, 3-12 h post-administration. Samples of blood, tumor, precancerous pouch tissue, normal pouch tissue and other clinically relevant normal tissues were processed for boron measurement by optic emission spectroscopy. Tumor boron concentration peaked to therapeutically useful boron concentration values of 24-35 ppm. The boron concentration ratio tumor/normal pouch tissue ranged from 1.1 to 1.8. Pharmacokinetic curves showed that the optimum interval between BSH administration and neutron irradiation was 7-11 h. It is concluded that BNCT mediated by BSH at nuclear reactor RA-3 would be feasible.
Assuntos
Boroidretos/farmacocinética , Terapia por Captura de Nêutron de Boro , Neoplasias Bucais/metabolismo , Compostos de Sulfidrila/farmacocinética , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinógenos , Cricetinae , Modelos Animais de Doenças , Mesocricetus , Neoplasias Bucais/induzido quimicamente , Distribuição TecidualRESUMO
Boron neutron capture therapy (BNCT) combines preferential tumor uptake of 10B compounds and neutron irradiation. Electroporation induces an increase in the permeability of the cell membrane. We previously demonstrated the optimization of boron biodistribution and microdistribution employing electroporation (EP) and decahydrodecaborate (GB-10) as the boron carrier in a hamster cheek pouch oral cancer model. The aim of the present study was to evaluate if EP could improve tumor control without enhancing the radiotoxicity of BNCT in vivo mediated by GB-10 with EP 10 min after GB-10 administration. Following cancerization, tumor-bearing hamster cheek pouches were treated with GB-10/BNCT or GB-10/BNCT + EP. Irradiations were carried out at the RA-3 Reactor. The tumor response and degree of mucositis in precancerous tissue surrounding tumors were evaluated for one month post-BNCT. The overall tumor response (partial remission (PR) + complete remission (CR)) increased significantly for protocol GB-10/BNCT + EP (92%) vs. GB-10/BNCT (48%). A statistically significant increase in the CR was observed for protocol GB-10/BNCT + EP (46%) vs. GB-10/BNCT (6%). For both protocols, the radiotoxicity (mucositis) was reversible and slight/moderate. Based on these results, we concluded that electroporation improved the therapeutic efficacy of GB-10/BNCT in vivo in the hamster cheek pouch oral cancer model without increasing the radiotoxicity.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias Bucais , Mucosite , Cricetinae , Animais , Terapia por Captura de Nêutron de Boro/métodos , Distribuição Tecidual , Boro , Neoplasias Bucais/radioterapia , Neoplasias Bucais/patologia , EletroporaçãoRESUMO
Boron neutron capture therapy (BNCT) is based on the preferential uptake of 10B compounds by tumors, followed by neutron irradiation. The aim of this study was to assess, in an ectopic colon cancer model, the therapeutic efficacy, radiotoxicity, abscopal effect and systemic immune response associated with (BPA/Borophenylalanine+GB-10/Decahydrodecaborate)-BNCT (Comb-BNCT) alone or in combination with Oligo-Fucoidan (O-Fuco) or Glutamine (GLN), compared to the "standard" BPA-BNCT protocol usually employed in clinical trials. All treatments were carried out at the RA-3 nuclear reactor. Boron biodistribution studies showed therapeutic values above 20 ppm 10B in tumors. At 7 weeks post-treatment, the ratio of tumor volume post-/pre-BNCT was significantly smaller for all BNCT groups vs. SHAM (p < 0.05). The parameter "incidence of tumors that underwent a reduction to ≤50% of initial tumor volume" exhibited values of 62% for Comb-BNCT alone, 82% for Comb-BNCT+GLN, 73% for Comb-BNCT+O-Fuco and only 30% for BPA-BNCT. For BPA-BNCT, the incidence of severe dermatitis was 100%, whereas it was significantly below 70% (p ≤ 0.05) for Comb-BNCT, Comb-BNCT+O-Fuco and Comb-BNCT+GLN. Considering tumors outside the treatment area, 77% of Comb-BNCT animals had a tumor volume lower than 50 mm3 vs. 30% for SHAM (p ≤ 0.005), suggesting an abscopal effect of Comb-BNCT. Inhibition of metastatic spread to lymph nodes was observed in all Comb-BNCT groups. Considering systemic aspects, CD8+ was elevated for Comb-BNCT+GLN vs. SHAM (p ≤ 0.01), and NK was elevated for Comb-BNCT vs. SHAM (p ≤ 0.05). Comb-BNCT improved therapeutic efficacy and reduced radiotoxicity compared to BPA-BNCT and induced an immune response and an abscopal effect.
RESUMO
Boron neutron capture therapy (BNCT) combines selective accumulation of (10)B carriers in tumor tissue with subsequent neutron irradiation. We previously demonstrated the therapeutic efficacy of BNCT in the hamster cheek pouch oral cancer model. Optimization of BNCT depends largely on improving boron targeting to tumor cells. Seeking to maximize the potential of BNCT for the treatment for head and neck cancer, the aim of the present study was to perform boron biodistribution studies in the oral cancer model employing two different liposome formulations that were previously tested for a different pathology, i.e., in experimental mammary carcinoma in BALB/c mice: (1) MAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a hypertonic buffer, administered intravenously at 6 mg B per kg body weight, and (2) MAC-TAC: liposomes incorporating K[nido-7-CH(3)(CH(2))(15)-7,8-C(2)B(9)H(11)] in the bilayer membrane and encapsulating a concentrated aqueous solution of the hydrophilic species Na(3) [ae-B(20)H(17)NH(3)], administered intravenously at 18 mg B per kg body weight. Samples of tumor, precancerous and normal pouch tissue, spleen, liver, kidney, and blood were taken at different times post-administration and processed to measure boron content by inductively coupled plasma mass spectrometry. No ostensible clinical toxic effects were observed with the selected formulations. Both MAC and MAC-TAC delivered boron selectively to tumor tissue. Absolute tumor values for MAC-TAC peaked to 66.6 ± 16.1 ppm at 48 h and to 43.9 ± 17.6 ppm at 54 h with very favorable ratios of tumor boron relative to precancerous and normal tissue, making these protocols particularly worthy of radiobiological assessment. Boron concentration values obtained would result in therapeutic BNCT doses in tumor without exceeding radiotolerance in precancerous/normal tissue at the thermal neutron facility at RA-3.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Boro/administração & dosagem , Boro/farmacocinética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/radioterapia , Animais , Cricetinae , Modelos Animais de Doenças , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Isótopos/administração & dosagem , Lipossomos/administração & dosagem , Lipossomos/farmacocinética , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/patologia , Distribuição TecidualRESUMO
Boron neutron capture therapy (BNCT) was proposed for untreatable colorectal liver metastases. The present study evaluates tumor control and potential radiotoxicity of BNCT in an experimental model of liver metastasis. BDIX rats were inoculated with syngeneic colon cancer cells DHD/K12/TRb. Tumor-bearing animals were divided into three groups: BPA-BNCT, boronophenylalanine (BPA) + neutron irradiation; Beam only, neutron irradiation; Sham, matched manipulation. The total absorbed dose administered with BPA-BNCT was 13 ± 3 Gy in tumor and 9 ± 2 Gy in healthy liver. Three weeks post-treatment, the tumor surface area post-treatment/pre-treatment ratio was 0.46 ± 0.20 for BPA-BNCT, 2.7 ± 1.8 for Beam only and 4.5 ± 3.1 for Sham. The pre-treatment tumor nodule mass of 48 ± 19 mg fell significantly to 19 ± 16 mg for BPA-BNCT, but rose significantly to 140 ± 106 mg for Beam only and to 346 ± 302 mg for Sham. For both end points, the differences between the BPA-BNCT group and each of the other groups were statistically significant (ANOVA). No clinical, macroscopic or histological normal liver radiotoxicity was observed. It is concluded that BPA-BNCT induced a significant remission of experimental colorectal tumor nodules in liver with no contributory liver toxicity.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Animais , Terapia por Captura de Nêutron de Boro/efeitos adversos , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Fígado/patologia , Fígado/efeitos da radiação , Masculino , Dosagem Radioterapêutica , Ratos , Resultado do TratamentoRESUMO
BACKGROUND: BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Although p-boronophenylalanine (BPA) has been clinically used, new boron compounds are needed for the advancement of BNCT. Based on previous studies in colon tumor-bearing mice, in this study, we evaluated MID:BSA (maleimide-functionalized closo-dodecaborate conjugated to bovine serum albumin) biodistribution and MID:BSA/BNCT therapeutic effect on tumors and associated radiotoxicity in the hamster cheek pouch oral cancer model. METHODS: Biodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue. RESULTS: MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity. CONCLUSIONS: MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied.
RESUMO
We previously demonstrated the therapeutic efficacy of different boron neutron capture therapy (BNCT) protocols in an experimental model of oral cancer. BNCT is based on the selective accumulation of (10)B carriers in a tumor followed by neutron irradiation. Within the context of exploring the potential therapeutic efficacy of BNCT for the treatment of liver metastases, the aim of the present study was to perform boron biodistribution studies in an experimental model of liver metastases in rats. Different boron compounds and administration conditions were assayed to determine which administration protocols would potentially be therapeutically useful in in vivo BNCT studies at the RA-3 nuclear reactor. A total of 70 BDIX rats were inoculated in the liver with syngeneic colon cancer cells DHD/K12/TRb to induce the development of subcapsular tumor nodules. Fourteen days post-inoculation, the animals were used for biodistribution studies. We evaluated a total of 11 administration protocols for the boron compounds boronophenylalanine (BPA) and GB-10 (Na(2)(10)B(10)H(10)), alone or combined at different dose levels and employing different administration routes. Tumor, normal tissue, and blood samples were processed for boron measurement by atomic emission spectroscopy. Six protocols proved potentially useful for BNCT studies in terms of absolute boron concentration in tumor and preferential uptake of boron by tumor tissue. Boron concentration values in tumor and normal tissues in the liver metastases model show it would be feasible to reach therapeutic BNCT doses in tumor without exceeding radiotolerance in normal tissue at the thermal neutron facility at RA-3.
Assuntos
Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Animais , Modelos Animais de Doenças , Feminino , Neoplasias Hepáticas/secundário , Masculino , RatosRESUMO
OBJECTIVE: The aim of the present study was to evaluate the local and regional therapeutic efficacy and abscopal effect of BNCT mediated by boronophenyl-alanine, combined with Bacillus Calmette-Guerin (BCG) as an immunotherapy agent in this model. METHODS: The local effect of treatment was evaluated in terms of tumor response in the irradiated tumor-bearing right hind flank. Metastatic spread to tumor-draining lymph nodes was analyzed as an indicator of regional effect. The abscopal effect of treatment was assessed as tumor growth inhibition in the contralateral (non-irradiated) left hind flank inoculated with tumor cells 2 weeks post-irradiation. The experimental groups BNCT, BNCT + BCG, BCG, Beam only (BO), BO +BCG, SHAM (tumor-bearing, no treatment, same manipulation) were studied. RESULTS: BNCT and BNCT + BCG induced a highly significant local anti-tumor response, whereas BCG alone induced a weak local effect. BCG and BNCT + BCG induced a significant abscopal effect in the contralateral non-irradiated leg. The BNCT + BCG group showed significantly less metastatic spread to tumor-draining lymph nodes vs SHAM and vs BO. CONCLUSION: This study suggests that BNCT + BCG-immunotherapy would induce local, regional and abscopal effects in tumor-bearing animals. BNCT would be the main effector of the local anti-tumor effect whereas BCG would be the main effector of the abscopal effect. ADVANCES IN KNOWLEDGE: Although the local effect of BNCT has been widely evidenced, this is the first study to show the local, regional and abscopal effects of BNCT combined with immunotherapy, contributing to comprehensive cancer treatment with combined therapies.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Neoplasias do Colo/terapia , Imunoterapia/métodos , Animais , Neoplasias do Colo/imunologia , Neoplasias do Colo/radioterapia , Terapia Combinada/métodos , Modelos Animais de Doenças , Feminino , Masculino , Ratos , Resultado do TratamentoRESUMO
Translational Boron Neutron Capture Therapy (BNCT) studies performed by our group and clinical BNCT studies worldwide have shown the therapeutic efficacy of BNCT for head and neck cancer. The present BNCT studies in veterinary patients with head and neck cancer were performed to optimize the therapeutic efficacy of BNCT, contribute towards exploring the role of BNCT in veterinary medicine, put in place technical aspects for an upcoming clinical trial of BNCT for head and neck cancer at the RA-6 Nuclear Reactor, and assess the feasibility of employing the existing B2 beam to treat large, deep-seated tumors. Five dogs with head and neck cancer with no other therapeutic option were treated with two applications of BNCT mediated by boronophenyl-alanine (BPA) separated by 3-5 weeks. Two to three portals per BNCT application were used to achieve a potentially therapeutic dose over the tumor without exceeding normal tissue tolerance. Clinical and Computed Tomography results evidenced partial tumor control in all cases, with slight-moderate mucositis, excellent life quality, and prolongation in the survival time estimated at recruitment. These exploratory studies show the potential value of BNCT in veterinary medicine and contribute towards initiating a clinical BNCT trial for head and neck cancer at the RA-6 clinical facility.
RESUMO
OBJECTIVE: The therapeutic success of different boron neutron capture therapy (BNCT) protocols employing the hamster cheek pouch oral cancer model has been previously reported by our laboratory. The aim of this study was to explore potential mechanisms of BNCT-induced damage to tumor in terms of potential inhibition in DNA synthesis and induction of apoptosis in the tumors that underwent partial remission following application of the different BNCT protocols in this model. MATERIALS AND METHODS: We evaluated DNA synthesis employing incorporation of 5-bromo-2'-deoxyuridine as an end-point. Apoptosis was evaluated by immunohistochemistry employing the deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling technique and Bax and Bcl-2 labeling. These studies were performed in tumors that underwent partial remission 1-30 days post-BNCT mediated by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) or (BPA + GB-10). RESULTS: BNCT exerted a marked inhibitory effect on DNA synthesis in tumors for all the protocols under study. The inhibitory effect of BPA-BNCT occurred as soon as 1 day post-treatment (P < 0.001). Conversely, the effect of GB-10-BNCT became apparent 7-14 days after therapy (P < 0.001) and was sustained until killed at 30 days post-treatment (P < 0.001). (GB-10 + BPA)-BNCT exerted a rapid and persistent effect, conceivably because of the combined effect of BNCT mediated by both boron compounds. The apoptosis studies did not show differences between the pre-treatment group and any of the BNCT groups. CONCLUSIONS: One of the mechanisms involved in BNCT-induced tumor control in our model would be an inhibitory effect on DNA synthesis. Apoptosis does not seem to have a significant role in BNCT-induced tumor control in our model.
Assuntos
Apoptose/efeitos da radiação , Terapia por Captura de Nêutron de Boro/métodos , DNA de Neoplasias/efeitos da radiação , Neoplasias Bucais/radioterapia , Neoplasias Experimentais/radioterapia , Animais , Compostos de Boro/uso terapêutico , Bochecha , Cricetinae , Modelos Animais de Doenças , Portadores de Fármacos , Marcação In Situ das Extremidades Cortadas , Mesocricetus , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Doses de Radiação , Radiossensibilizantes , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
Boron neutron capture therapy (BNCT) is a targeted therapy, which consists of preferential accumulation of boron carriers in tumor followed by neutron irradiation. Each oral cancer patient has different risks of developing one or more carcinomas and/or oral mucositis induced after treatment. Our group proposed the hamster oral cancer model to study the efficacy of BNCT and associated mucositis. Translational studies are essential to the advancement of novel boron delivery agents and targeted strategies. Herein, we review our work in the hamster model in which we studied BNCT induced mucositis using three different cancerization protocols, mimicking three different clinical scenarios. The BNCT-induced mucositis increases with the aggressiveness of the carcinogenesis protocol employed, suggesting that the study of different oral cancer patient scenarios would help to develop personalized therapies.