ABSTRACT
Undifferentiated thyroid cancer (UTC) is a very aggressive tumor with no effective treatment, since it lacks iodine uptake and does not respond to radio or chemotherapy. The prognosis of these patients is bad, due to the rapid growth of the tumor and the early development of metastasis. Boron neutron capture therapy (BNCT) is based on the selective uptake of certain boron non-radioactive compounds by a tumor, and the subsequent irradiation of the area with an appropriate neutron beam. 10B is then activated to 11B, which will immediately decay releasing alpha particles and 7Li, of high linear energy transfer (LET) and limited reach. Clinical trials are being performed in patients with glioblastoma multiforme and melanoma. We have explored its possible application to UTC. Our results demonstrated that a cell line of human UTC has a selective uptake of borophenylalanine (BPA) both in vitro and after transplantation to nude mice. Treatment of mice by BNCT led to a complete control of growth and cure of 100 percent of the animals. Moreover dogs with spontaneous UTC also have a selective uptake of BPA. At the present we are studying the biodistribution of BPA in patients with UTC before its application in humans.
O câncer indiferenciado de tiróide (CIT) é um tumor muito agressivo sem tratamento efetivo, uma vez que não capta iodo e não responde à radio ou quimioterapia. O prognóstico desses pacientes é ruim, devido ao rápido crescimento do tumor e surgimento precoce de metástases. A terapia por captura de nêutrons de boro (TCNB) é baseada na captação seletiva de certos compostos de boro não-radioativos pelo tumor, e à subsequente irradiação da área com um feixe de nêutrons apropriado. O 10B é então ativado para 11B, cujo decaimento imediato libera partículas alfa e 7Li, de alta transferência linear de energia (TLE) e alcance limitado. Ensaios clínicos estão sendo conduzidos em pacientes com glioblastoma multiforme e melanoma, e nós estamos explorando sua possível aplicação no CIT. Nossos resultados demonstram que uma linhagem celular do CIT humano mostra captação seletiva de borofenilalanina (BPA) tanto in vitro como após transplante em camundongos "nude". O tratamento de camundongos com TCNB leva a um controle completo do crescimento tumoral e à cura em 100 por cento dos animais. Além disso, cães com CIT espontâneo também apresentam captação seletiva de BPA. No momento, estamos estudando a biodistribuição de BPA em pacientes com CIT, antes de sua aplicação em humanos.
Subject(s)
Animals , Dogs , Humans , Mice , Boron Compounds/therapeutic use , Boron Neutron Capture Therapy/trends , Radiation-Sensitizing Agents/therapeutic use , Thyroid Neoplasms/radiotherapy , Boron Compounds/pharmacokinetics , Boron Neutron Capture Therapy/methods , Cell Line, Tumor , Disease Models, Animal , Deuteroporphyrins/therapeutic use , Mice, Nude , Phenylalanine/analogs & derivatives , Phenylalanine/therapeutic use , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathologyABSTRACT
El cáncer indiferenciado de tiroides es un tumor muy agresivo, de muy mal pronóstico y sin tratamiento efectivo. La terapia por captura neutrónica de boro (BNCT) podría ser una alternativa para el tratamiento de esta enfermedad. Se basa en la captación selectiva de boro por el tumor y su activación por un haz de neutrones. El boro activado libera un núcleo de litio-7 y una partícula alfa, las cuales tienen una alta transmisión linear de energía (linear energy transfer, LET) y un alcance de 5-9 µm, destruyendo el tumor. En estudios previos hemos mostrado que la línea celular humana de cáncer indiferenciado de tiroides (ARO) tiene una captación selectiva de borofenilalanina (10BPA) tanto in vitro como después de ser implantada en ratones NIH nude. También demostramos en estos animales inyectados con BPA e irradiados con un haz de neutrones térmicos, un 100% de control sobre el crecimiento tumoral y un 50% de cura histológica. En trabajos posteriores mostramos que la porfirina 10BOPP tetrakis-carborane carboxylate ester de 2,4-bis-(a,b-dihydroxyethyl)-deutero-porphyrin IX) cuando es inyectada 5-7 días antes que el BPA se obtiene una concentración tumoral de boro de aproximadamente el doble que el BPA solo (45-38 ppm vs. 20 ppm). La posterior irradiación con neutrones mostró un 100% de remisión completa en animales con tumores cuyo volumen pre-tratamiento era de 50 mm3 o menor. Los perros padecen CIT espontáneo, con un comportamiento biológico similar al humano, y una captación selectiva de BPA, abriendo la posibilidad de su tratamiento por BNCT
Undifferentiated thyroid carcinoma (UTC) is an aggressive tumor with a poor prognosis due to the lack of an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of boron by the tumor and its activation by a neutron beam, releasing lithium-7 and an alpha particle that will kill the tumor cells by their high linear energy transfer (LET). In previous studies we have shown a selective uptake of borophenylalanine (10BPA) in a human UTC cell line (ARO) and in NIH nude mice implanted with this cell line. When these animals were injected with BPA and irradiated with an appropriated neutron beam, we observed a 100% of tumor growth control and a 50 % of histological cure when the initial tumor volume was 50 mm3 or less. Further studies with BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(a, b-dihydroxyethyl)-deutero-porphyrin IX) showed that when this porphyrin was injected 5-7 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (45-38 ppm with both compounds vs. 20 ppm with BPA alone). The application of BNCT using the combination of boron compounds showed a 100% of complete remission in tumors with initial volumes under 50 mm3. Dogs suffer spontaneous UTC, with a similar biological behavior to the human tumor, and a selective uptake of BPA. These results open the possibility of applying BNCT to UTC
Subject(s)
Humans , Animals , Male , Female , Adolescent , Adult , Middle Aged , Aged, 80 and over , Dogs , Mice , Benzoates , Boron Neutron Capture Therapy , Boron Compounds/therapeutic use , Carcinoma, Squamous Cell/radiotherapy , Sulfhydryl Compounds/therapeutic use , Thyroid Neoplasms/radiotherapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzoates , Boron Compounds/pharmacology , Cell Line/drug effects , Linear Energy Transfer/drug effects , Mice, Nude , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Phenylalanine/therapeutic use , Sulfhydryl Compounds/pharmacologyABSTRACT
The plasma kallikrein-kinin system (KKS) participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion and release of proteases. It has been shown that KKS activation in the systemic inflammatory response syndrome results in decrease of its component plasma proteins. Similar changes have been documented in diabetes, sepsis, children with vasculitis, allograft rejection, disseminated intravascular coagulation, patients with recurrent pregnancy losses, hereditary angioedema, adult respiratory distress syndrome and coronary artery disease. Direct involvement of the KKS in the pathogenesis of experimental acute arthritis and acute and chronic enterocolitis has been documented by previous studies from our laboratory using experimental animal models. It has been found that in HK deficient Lewis rats, experimental IBD was much less severe. We showed a genetic difference in kininogen structure between resistant Buffalo and susceptible Lewis rats, which results in accelerated cleavage of HK and it is responsible for the susceptibility to the inflammatory process in the Lewis rats. It has been demostrated that therapy with a specific plasma kallikrein inhibitor (P8720) modulated the experimental enterocolitis, arthritis and systemic inflammation. Furthermore, it has been shown that a bradykinin 2 receptor (B2R) antagonist attenuates the inflammatory changes in the same animal model. We have showed that a monoclonal antibody targeting HK decreases angiogénesis and arrests tumor growth in a syngeneic animal model. In summary, these results indicate that the plasma KKS plays a central role in the pathogenesis of chronic intestinal inflammation, arthritis and angiogenesis.
Se ha demostrado la participación del sistema plasmático de kalikreína-kininas (KKS) en el proceso inflamatorio, el cual incluye reacciones de daño celular, coagulación y fibrinólisis, formación de kininas, activación del complemento, secreción de citoquinas y liberación de proteasas. El KKS se encuentra activado en el síndrome de respuesta inflamatoria sistémica con una disminución en la concentración plasmática de las proteínas que lo constituyen. También se ha demostrado una activación similar en la diabetes, choque séptico, vasculitis en infantes, enfermedad injerto-huésped, coagulación intravascular diseminada, pacientes con abortos de repetición, angioedema hereditario, el síndrome de estrés respiratorio del adulto y enfermedad coronaria arterial. Mediante el uso de modelos animales experimentales, nuestro laboratorio ha demostrado una participación directa del KKS en la patogénesis de la artritis experimental aguda y la enterocolitis aguda y crónica. Se ha demostrado que en la rata tipo Lewis, cuando es deficiente de kininógeno de alto peso molecular (HK), la enfermedad inflamatoria intestinal es menos severa comparada con la presentada en ratas con niveles normales de HK como la Buffalo. Nosotros mostramos una diferencia entre el gene que codifica la molécula del kininógeno de la rata tipo Buffalo (resistentes) y Lewis (susceptibles), que resulta en un incremento de la actividad proteolítica de kalikreína sobre su substrato HK, lo cual predispone a las ratas Lewis al desarrollo de la enfermedad inflamatoria crónica. Se ha demostrado una disminución en las manifestaciones inflamatorias sistémicas de la enterocolitis y artritis experimental mediante el uso de un inhibidor específico de la kalikreína (P8720). Además, el antagonista del receptor 2 de la bradikinina (BR2) atenuó los cambios inflamatorios en el mismo modelo animal. Asimismo, se ha demostrado que las ratas Lewis deficientes de kininógeno desarrollaron inflamación intestinal sistémica menos severa. Mediante el uso del anticuerpo monoclonal C11C1 contra HK se logró una disminución de la angiogenesis y, consecuentemente, el crecimiento tumoral. En conclusión, los resultados demuestran que el sistema plasmático de KKS desempeña un papel preponderante en la patogénesis de la artritis reumatoide, la enfermedad intestinal crónica y en el proceso angiogénico.