RESUMO
Sodium mercaptoundecahydro-closo-dodecaborate (BSH) is being investigated clinically for BNCT. We examined the biodistribution of BSH and BPA administered jointly in different proportions in the hamster cheek pouch oral cancer model. The 3 assayed protocols were non-toxic, and showed preferential tumor boron uptake versus precancerous and normal tissue and therapeutic tumor boron concentration values (70-85ppm). All 3 protocols warrant assessment in BNCT studies to contribute to the knowledge of (BSH+BPA)-BNCT radiobiology for head and neck cancer and optimize therapeutic efficacy.
Assuntos
Boroidretos/administração & dosagem , Boroidretos/farmacocinética , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Terapia por Captura de Nêutron de Boro/métodos , Neoplasias Bucais/metabolismo , Neoplasias Bucais/radioterapia , Fenilalanina/análogos & derivados , Compostos de Sulfidrila/administração & dosagem , Compostos de Sulfidrila/farmacocinética , Animais , Bochecha , Cricetinae , Combinação de Medicamentos , Mesocricetus , Taxa de Depuração Metabólica , Especificidade de Órgãos , Fenilalanina/administração & dosagem , Fenilalanina/farmacocinética , Dosagem Radioterapêutica , Distribuição Tecidual , Resultado do TratamentoRESUMO
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
We previously demonstrated the efficacy of boron neutron capture therapy (BNCT) mediated by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and (GB-10+BPA) to control tumors, with no normal tissue radiotoxicity, in the hamster cheek pouch oral cancer model. Herein we developed a novel experimental model of field-cancerization and precancerous lesions (globally termed herein precancerous tissue) in the hamster cheek pouch to explore the long-term potential inhibitory effect of the same BNCT protocols on the development of second primary tumors from precancerous tissue. Clinically, second primary tumor recurrences occur in field-cancerized tissue, causing therapeutic failure. We performed boron biodistribution studies followed by in vivo BNCT studies, with 8 months follow-up. All 3 BNCT protocols induced a statistically significant reduction in tumor development from precancerous tissue, reaching a maximum inhibition of 77-100%. The inhibitory effect of BPA-BNCT and (GB-10+BPA)-BNCT persisted at 51% at the end of follow-up (8 months), whereas for GB-10-BNCT it faded after 2 months. Likewise, beam-only elicited a significant but transient reduction in tumor development. No normal tissue radiotoxicity was observed. At 8 months post-treatment with BPA-BNCT or (GB-10+BPA)-BNCT, the precancerous pouches that did not develop tumors had regained the macroscopic and histological appearance of normal (non-cancerized) pouches. A potential new clinical application of BNCT would lie in its capacity to inhibit local regional recurrences.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Lesões Pré-Cancerosas/radioterapia , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Boroidretos/farmacocinética , Boroidretos/uso terapêutico , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Cricetinae , Neoplasias Bucais/radioterapia , Recidiva Local de Neoplasia/radioterapia , Segunda Neoplasia Primária/radioterapia , Fenilalanina/análogos & derivados , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/uso terapêutico , Compostos de Sulfidrila/farmacocinética , Compostos de Sulfidrila/uso terapêutico , Distribuição TecidualRESUMO
OBJECTIVE: BNCT is a tumour cell targeted radiation therapy. Uniform targeting of heterogeneous tumours with therapeutically effective boron carriers would contribute to a therapeutic effect on all tumour cell populations and avoid radioresistant fractions. This remains an unresolved challenge. The aim of the present study was to evaluate the degree of variation in boron content delivered by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and the combined administration of (BPA+GB-10) in different portions of tumour, precancerous tissue around tumour and normal pouch tissue in the hamster cheek pouch oral cancer model. MATERIALS AND METHODS: Samples of different areas of tumour, precancerous tissue and normal pouch tissue were taken from tumour-bearing hamsters, 3h post-administration of i.p. BPA (15.5mg B/kg b.w.), or i.v. GB-10 (50mg B/kg b.w.), or 3h and 1.5h post-administration respectively of i.v. GB-10 (34.5mg B/b.w.) and sequential i.p. injections of BPA (total dose 31mg B/kg b.w.) given jointly. Boron content was evaluated by inductively coupled plasma optical emission spectroscopy (ICP-OES). The degree of homogeneity in boron targeting was assessed in terms of the coefficient of variation (V: [S.D./mean]x100) of boron values. Statistical analysis of the results was performed by one-way ANOVA and the least significant difference test. RESULTS: GB-10 and GB-10 plus BPA achieved respectively a statistically significant 1.8- and 3.3-fold increase in targeting homogeneity over BPA. CONCLUSIONS: The combined boron compound administration protocol contributes to homogeneous targeting of heterogeneous tumours and would be expected to increase therapeutic efficacy of BNCT.