ABSTRACT
The relationship between ligand-receptor affinity and antitumor potency of an oncolytic virus was investigated using a panel of six HER2/neu (HER2)-targeted measles viruses (MVs) displaying single-chain antibodies (scFv) that bind to the same epitope on HER2, but with affinities ranging from 10(-6) to 10(-11) M. All viruses were able to infect SKOV3ip.1 human ovarian cancer cells in vitro, but only the high-affinity MV (Kd≥10(-8) M) induced cytopathic effects of syncytia formation in the cell monolayers. In contrast, all six viruses were therapeutically active in vivo against orthotopic human ovarian SKOV3ip.1 tumor xenografts in athymic mice compared with saline-treated controls. The oncolytic activities of MV displaying the high-affinity scFv (Kd=10(-9), 10(-10), 10(-11) M) were not significantly superior to MV displaying scFv with Kd of 10(-8) M or less. Results from this study suggest that increasing the receptor affinity of the attachment protein of an oncolytic MV has minimal impact on its in vivo efficacy against a tumor that expresses the targeted receptor.
Subject(s)
Measles virus/immunology , Oncolytic Virotherapy/methods , Oncolytic Viruses/immunology , Single-Chain Antibodies/metabolism , Animals , Disease Models, Animal , Epitopes/metabolism , Female , Humans , Injections, Intraperitoneal , Mice, Nude , Oncolytic Viruses/pathogenicity , Ovarian Neoplasms/virology , Receptor, ErbB-2/metabolism , Spheroids, Cellular/virology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Sodium iodide symporter (NIS) reporter gene imaging is an excellent technology for noninvasive cell fate determination in living animals unless the NIS-transduced cells reside in perigastric organs such as the spleen, liver, diaphragm, omentum, pancreas, perigastric lymph nodes or perigastric tumor deposits. Here we report that orally administered barium sulfate enhances CT definition of the stomach, masks background gamma ray emissions from the stomach and enhances signal detection from radiotracer uptake in NIS-transduced organs.
Subject(s)
Barium Sulfate , Contrast Media , Genes, Reporter/drug effects , Iodine Radioisotopes , Symporters/genetics , Animals , Barium Sulfate/administration & dosage , Cell Line, Tumor , Contrast Media/administration & dosage , Female , Gene Transfer Techniques , Heterografts , Humans , Iodine Radioisotopes/administration & dosage , Mice , Mice, Nude , Multimodal Imaging/methods , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/diagnostic imaging , Ovarian Neoplasms/pathology , Stomach/anatomy & histology , Stomach/diagnostic imaging , Symporters/metabolism , Tomography, Emission-Computed, Single-Photon/methods , Tomography, X-Ray Computed/methodsABSTRACT
Oncolytic vesicular stomatitis virus (VSV) has potent antitumor activity but some cancer cells are resistant to VSV killing, either constitutively or due to type I interferon (IFN) inducing an antiviral state in the cells. Here, we evaluated VSV oncolysis of a panel of human head and neck cancer cells and showed that VSV resistance in SCC25 and SCC15 cells could be reversed with Janus kinase (JAK) 1/2 inhibitors (JAK inhibitor I and ruxolitinib). Pre-treatment of cells with JAK1/2 inhibitors before or in conjunction with VSV enhanced viral infection, spread and progeny yield (100- to 1000-fold increase). In contrast, inhibitors of histone deacetylase (LBH589), phosphatidylinositol 3-kinase (GDC-0941, LY294002), mammalian target of rapamycin (rapamycin) or signal transducer and activator of transcription 3 (STAT3 inhibitor VII) were ineffective. Compared with VSV-sensitive SW579 cells, IFNα/ß responsive antiviral genes (IRF-9, IRF-7, OAS1 but not MxA) are constitutively expressed in SCC25 cells. Pretreatment with JAK inhibitors reduced mRNA levels of these genes, increasing VSV expression in the cells. Interestingly, 1 h of drug exposure was sufficient to reverse SCC25 resistance to VSV and was still effective if virus was added 24 h later. Overall, we show here that JAK inhibitor I and ruxolitinib (Jakafi) can reverse resistance to VSV, supporting the rationale to incorporate JAK1/2 inhibitors in future VSV virotherapy trials.
