Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenoviridae / genetics
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Animals
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Antineoplastic Agents, Alkylating / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Brain Neoplasms / drug therapy
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Brain Neoplasms / genetics
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Brain Neoplasms / therapy*
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Brain Neoplasms / virology
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Cell Growth Processes / genetics
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Cell Line, Tumor
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Combined Modality Therapy
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Dacarbazine / analogs & derivatives*
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Dacarbazine / pharmacology
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Female
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Genetic Therapy / methods
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Genetic Vectors / genetics
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Glioma / drug therapy
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Glioma / genetics
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Glioma / therapy*
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Glioma / virology
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Humans
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Interleukins / genetics*
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Mice
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Mice, Nude
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Oncolytic Virotherapy / methods*
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Promoter Regions, Genetic
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Recombinant Proteins / pharmacology
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Temozolomide
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Vascular Endothelial Growth Factor A / pharmacology
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Vascular Endothelial Growth Factor Receptor-1 / biosynthesis
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Vascular Endothelial Growth Factor Receptor-1 / genetics*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Alkylating
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Interleukins
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Recombinant Proteins
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Vascular Endothelial Growth Factor A
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interleukin-24
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Dacarbazine
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Vascular Endothelial Growth Factor Receptor-1
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Temozolomide