RESUMEN
The aim of this study was to evaluate the enhancement of the efficacy of systemic doxorubicin by pulsed high-intensity focused ultrasound (HIFU)-induced, localized mild hyperthermia. For the in vitro study, the intranuclear uptake of doxorubicin by squamous cell carcinoma (SCC)-7 cells incubated at different temperatures was compared. For the in vivo study, mice with SCC-7 tumors were assigned to either the control, conventional hyperthermia, HIFU hyperthermia, doxorubicin-alone, conventional hyperthermia + doxorubicin or HIFU hyperthermia + doxorubicin group. Conventional hyperthermia was induced by immersing the tumor in warm water (42.5°C), and HIFU hyperthermia was induced by HIFU after optimizing the parameters with direct temperature measurements (frequency = 1 MHz, pulse repetition frequency = 5 Hz, power = 12 W, duty cycle = 50%). In the in vitro study, fluorescence was more intense at 42°C than at 37°C and was time dependent. In the in vivo study, tumor growth in the HIFU hyperthermia + doxorubicin group was most prominently suppressed with the highest apoptotic index compared with all other groups (p < 0.05). Pulsed HIFU-induced localized mild hyperthermia enhanced the anti-cancer efficacy of systemic doxorubicin more than conventional mild hyperthermia.
Asunto(s)
Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Doxorrubicina/administración & dosificación , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Hipertermia Inducida/métodos , Animales , Antibióticos Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Terapia Combinada/métodos , Sinergismo Farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Resultado del TratamientoRESUMEN
Our aim was to evaluate whether pulsed high-intensity focused ultrasound (HIFU) therapy enhances the effect of an epidermal growth factor receptor-targeted chemotherapeutic drug, cetuximab, in treating human colon cancer xenografts in a mouse model. Balb/c nude mice with subcutaneous xenografts of HT-29 cells were randomly categorized into control (n = 9), pulsed HIFU alone (n = 10), cetuximab monotherapy (n = 8) or combined pulsed HIFU and cetuximab therapy (n = 9) group. Cetuximab, pulsed HIFU therapy, or both were administered three times per week starting from day 8 after tumor cell injection. Based on tumor growth curves up to 34 days, the combination therapy group showed more suppressed tumor growth than all other groups (p < 0.05). The final relative tumor volumes were 5.4 ± 2.1, 5.2 ± 1.3, 4.8 ± 1.8, and 3.1 ± 0.9 for control, pulsed HIFU alone, cetuximab monotherapy, and combination therapy groups, respectively. In conclusion, pulsed HIFU therapy appears to enhance the anti-tumor effect of epidermal growth factor receptor-targeted cetuximab on human colon cancer xenograft models in mice.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias del Colon/tratamiento farmacológico , Modelos Animales de Enfermedad , Electroquimioterapia/métodos , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Cetuximab , Neoplasias del Colon/diagnóstico por imagen , Células HT29 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Resultado del Tratamiento , UltrasonografíaRESUMEN
Angiogenesis inhibition is an attractive therapeutic strategy in the management of solid tumors. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are key factors in growth and neovascularization of hepatocellular carcinoma (HCC). Brivanib is a novel, orally available dual tyrosine kinase inhibitor that selectively targets the key angiogenesis receptors VEGFR2, FGFR1 and FGFR2. Recently, highresolution magic angle spinning magnetic resonance spectroscopy (HRMAS MRS) has provided the opportunity to investigate more detailed metabolic profiles from intact tissue specimens that are correlated with histopathology and is thus, a promising tool for monitoring changes induced by treatment. In the present study, 1H HRMAS MRS and immunohistochemistry were used to investigate the antitumor efficacy of brivanib in HCC xenograft models. Tumor growth was significantly suppressed in brivanibtreated mice compared with the controls and treatment was associated with the inhibition of angiogenesis, increased apoptosis and inhibition of cell proliferation. Furthermore, HRMAS techniques showed altered metabolic profiles between the two groups. HRMAS spectra demonstrated a significant decrease in choline metabolite levels in the treated groups, concurrent with decreased cell proliferation and increased apoptosis. The results showed that 1H HRMAS MRS provides quantitative metabolite information that may be used to analyze the efficacy of brivanib treatment in Hep3B tumor xenografts. Thus, the HRMAS MRS technique may be a complementary method to support histopathological results and increase its potential for use in the clinic.