RESUMEN
Malignant forms of glioma, the most common primary brain tumors, remain poorly responsive to multimodality therapeutic interventions, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are important distinctive features that contribute to the malignant phenotype of glioma. We have developed the vascular endothelial growth factor receptor 1 (VEGFR-1/flt-1) conditional replicating adenoviral vector (CRAdRGDflt-IL24) encoding the interleukin-24 (IL-24) gene. We investigated whether a combination of CRAdRGDflt-IL24-mediated oncolytic virotherapy and chemotherapy using temozolomide (TMZ) produces increased cytotoxicity against human glioma cells in comparison with these agents alone. Combination of CRAdRGDflt-IL24 and TMZ significantly enhanced cytotoxicity in vitro, inhibited D54MG tumor growth and prolonged survival of mice harboring intracranial human glioma xenografts in comparison with CRAdRGDflt-IL24 or TMZ alone. These data indicate that combined treatment with CRAdRGDflt-IL24-mediated oncolytic virotherapy and TMZ chemotherapy provides a promising approach for glioma therapy.
Asunto(s)
Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Glioma/terapia , Interleucinas/genética , Viroterapia Oncolítica/métodos , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Adenoviridae/genética , Animales , Antineoplásicos Alquilantes/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/virología , Procesos de Crecimiento Celular/genética , Línea Celular Tumoral , Terapia Combinada , Dacarbazina/farmacología , Femenino , Terapia Genética/métodos , Vectores Genéticos/genética , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/virología , Humanos , Ratones , Ratones Desnudos , Regiones Promotoras Genéticas , Proteínas Recombinantes/farmacología , Temozolomida , Factor A de Crecimiento Endotelial Vascular/farmacología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Combined treatment using adenoviral (Ad)-directed enzyme/prodrug therapy and radiation therapy has the potential to become a powerful method of cancer therapy. We have developed an Ad vector encoding a mutant bacterial cytosine deaminase (bCD) gene (AdbCD-D314A), which has a higher affinity for cytosine than wild-type bCD (bCDwt). The purpose of this study was to evaluate cytotoxicity in vitro and therapeutic efficacy in vivo of the combination of AdbCD-D314A with the prodrug 5-fluorocytosine (5-FC) and ionizing radiation against human glioma. The present study demonstrates that AdbCD-D314A infection resulted in increased 5-FC-mediated cell killing, compared with AdbCDwt. Furthermore, a significant increase in cytotoxicity following AdbCD-D314A and radiation treatment of glioma cells in vitro was demonstrated as compared to AdbCDwt. Animal studies showed significant inhibition of subcutaneous or intracranial tumor growth of D54MG glioma xenografts by the combination of AdbCD-D314A/5-FC with ionizing radiation as compared with either agent alone, and with AdbCDwt/5-FC plus radiation. The results suggest that the combination of AdbCD-D314A/5-FC with radiation produces markedly increased cytotoxic effects in cancer cells in vitro and in vivo. These data indicate that combined treatment with this novel mutant enzyme/prodrug therapy and radiotherapy provides a promising approach for cancer therapy.
Asunto(s)
Adenoviridae/genética , Neoplasias Encefálicas/terapia , Citosina Desaminasa/genética , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Glioma/terapia , Animales , Antimetabolitos/uso terapéutico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Terapia Combinada , Citosina/metabolismo , Citosina Desaminasa/metabolismo , Escherichia coli/enzimología , Flucitosina/uso terapéutico , Genes Transgénicos Suicidas , Vectores Genéticos/genética , Glioma/diagnóstico por imagen , Glioma/metabolismo , Humanos , Ratones , Ratones Desnudos , Mutación , Trasplante de Neoplasias , Profármacos/uso terapéutico , Radiografía , Trasplante HeterólogoRESUMEN
Combined treatment using adenoviral-directed enzyme/prodrug therapy and immunotherapy has the potential to become a powerful alternative method of cancer therapy. We have developed adenoviral vectors encoding the cytosine deaminase gene (Ad-CD) and cytosine deaminase:uracil phosphoribosyltransferase fusion gene (Ad-CD:UPRT). A monoclonal antibody, TRA-8, specifically binds to death receptor 5, one of two death receptors bound by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The purpose of this study was to evaluate cytotoxicity in vitro and therapeutic efficacy in vivo of the combination of Ad-CD:UPRT and TRA-8 against human pancreatic cancer and glioma cell lines. The present study demonstrates that Ad-CD:UPRT infection resulted in increased 5-FC-mediated cell killing, compared with Ad-CD. Furthermore, a significant increase of cytotoxicity following Ad-CD:UPRT/5-FC and TRA-8 treatment of cancer cells in vitro was demonstrated. Animal studies showed significant inhibition of tumor growth of MIA PaCa-2 pancreatic and D54MG glioma xenografts by the combination of Ad-CD:UPRT/5-FC plus TRA-8 as compared with either agent alone or no treatment. The results suggest that the combination of Ad-CD:UPRT/5-FC with TRA-8 produces an additive cytotoxic effect in cancer cells in vitro and in vivo. These data indicate that combined treatment with enzyme/prodrug therapy and TRAIL immunotherapy provides a promising approach for cancer therapy.