Abstract
BackgroundInterferon-γ (IFN-γ) is regarded as a potent antitumor agent, but its clinical application is limited by its short half-life and significant side effects. In this paper, we tried to develop IFN-γ gene therapy by a replication defective adenovirus encoding the human IFN-γ (Ad-IFNγ), and evaluate the antitumoral effects of Ad-IFNγ on nasopharyngeal carcinoma (NPC) cell lines in vitro and in xenografts model.MethodsThe mRNA levels of human IFN-γ in Ad-IFNγ-infected NPC cells were detected by reverse transcription-polymerase chain reaction (RT-PCR), and IFN-γ protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the culture supernatants of NPC cells and tumor tissues and bloods of nude mice treated with Ad-IFNγ. The effects of Ad-IFNγ on NPC cell proliferation was determined using MTT assay, cell cycle distribution was determined by flow cytometry analysis for DNA content, and cells apoptosis were analyzed by Annexin V-FITC/7-AAD binding assay and hoechst 33342/PI double staining. The anti-tumor effects and toxicity of Ad-IFNγ were evaluated in BALB/c nude mice carrying NPC xenografts.ResultsThe results demonstrated that Ad-IFNγ efficiently expressed human IFN-γ protein in NPC cell lines in vitro and in vivo. Ad-IFNγ infection resulted in antiproliferative effects on NPC cells by inducing G1 phase arrest and cell apoptosis. Intratumoral administration of Ad-IFNγ significantly inhibited the growth of CNE-2 and C666-1 cell xenografts in nude mice, while no significant toxicity was observed.ConclusionsThese findings indicate IFN-γ gene therapy mediated by replication defective adenoviral vector is likely a promising approach in the treatment of nasopharyngeal carcinoma.
Highlights
Interferon-γ (IFN-γ) is regarded as a potent antitumor agent, but its clinical application is limited by its short half-life and significant side effects
adenovirus encoding the human IFN-γ (Ad-IFNγ) efficiently expressed hIFNγ in NPC cells To evaluate the capability of Ad-IFNγ expressed transgenic product in nasopharyngeal carcinoma (NPC) cells, we firstly investigated IFNγ mRNA levels in CNE-2 cells after Ad-IFNγ infection at different multiplicities of infection (MOIs) at different time
The results showed that Ad-IFNγ efficiently transcribed human IFNγ gene in CNE-2 cells at a dose-dependent manner (Figure 1A), hIFNγ mRNA was detected as early as 8 hours after Ad-IFNγ infection, the levels reached the top at 48 hours after infection, and gradually decreased, while No IFNγ mRNA was detected in A replication defective adenovirus encoding β-galactosidase (Ad-LacZ)-infected cells (Figure 1B)
Summary
Interferon-γ (IFN-γ) is regarded as a potent antitumor agent, but its clinical application is limited by its short half-life and significant side effects. We tried to develop IFN-γ gene therapy by a replication defective adenovirus encoding the human IFN-γ (Ad-IFNγ), and evaluate the antitumoral effects of Ad-IFNγ on nasopharyngeal carcinoma (NPC) cell lines in vitro and in xenografts model. Nasopharyngeal carcinoma (NPC) is a rare tumor arising from the epithelium of the nasopharynx. It has a high incidence rate in South China and Southeast Asia [1]. The poor survival is often associated with high incidences of local, regional and systemic recurrences. Concurrent chemoradiotherapy is developed as a standard treatment approach for advanced NPC, the outcome isn’t still satisfactory [3]. The development of multidisciplinary therapeutic approaches is crucial for improvement of survival in NPC patients
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