Abstract
BackgroundGene therapy using a recombinant adenovirus (Ad) encoding secretory human endostatin (Ad-Endo) has been demonstrated to be a promising antiangiogenesis and antitumor strategy of in animal models and clinical trials. The E1B55KD-deficient Ad dl1520 was also found to replicate selectively in and destroy cancer cells. In this study, we aimed to investigate the antitumor effects of antiangiogenic agent Ad-Endo combined with the oncolytic Ad dl1520 on gastric cancer (GC) in vitro and in vivo and determine the mechanisms of these effects.MethodsThe Ad DNA copy number was determined by real-time PCR, and gene expression was assessed by ELISA, Western blotting or immunohistochemistry. The anti-proliferation effect (cytotoxicity) of Ad was assessed using the colorimetry-based MTT cell viability assay. The antitumor effects were evaluated in BALB/c nude mice carrying SGC-7901 GC xenografts. The microvessel density and Ad replication in tumor tissue were evaluated by checking the expression of CD34 and hexon proteins, respectively.Resultsdl1520 replicated selectively in GC cells harboring an abnormal p53 pathway, including p53 mutation and the loss of p14ARF expression, but did not in normal epithelial cells. In cultured GC cells, dl1520 rescued Ad-Endo replication, and dramatically promoted endostatin expression by Ad-Endo in a dose- and time-dependent manner. In turn, the addition of Ad-Endo enhanced the inhibitory effect of dl1520 on the proliferation of GC cells. The transgenic expression of Ad5 E1A and E1B19K simulated the rescue effect of dl1520 supporting Ad-Endo replication in GC cells. In the nude mouse xenograft model, the combined treatment with dl1520 and Ad-Endo significantly inhibited tumor angiogenesis and the growth of GC xenografts through the increased endostatin expression and oncolytic effects.ConclusionsAd-Endo combined with dl1520 has more antitumor efficacy against GC than Ad-Endo or dl1520 alone. These findings indicate that the combination of Ad-mediated antiangiogenic gene therapy and oncolytic Ad therapeutics could be one of promising comprehensive treatment strategies for GC.
Highlights
Gastric cancer (GC) is one of the most common malignancies and a leading cause of cancer-related mortality worldwide, especially in Asian countries [1,2,3]
The results indicate that dl1520 enhanced the antiangiogenic effect of Ad-Endo by rescuing the replication of Ad-Endo, thereby dramatically increasing endostatin expression, when Ad-Endo in turn enhanced the oncolytic effect of dl1520 by reinforcing viral replication in GC cells
The endostatin amount increased along with the increases in the dl1520 doses when cells were infected with Ad-Endo at a constant dose (10 Multiplicity of infection (MOI)) (Figure 3B). These results indicated that dl1520 promoted the expression of endostatin by rescuing Ad-Endo replication in GC cells
Summary
Gastric cancer (GC) is one of the most common malignancies and a leading cause of cancer-related mortality worldwide, especially in Asian countries [1,2,3]. Antiangiogenic therapy is an attractive strategy for the treatment of cancer [9,10,11,12]. The high instability and shorter serum half-life of the recombinant endostatin protein made it inappropriate or inconvenient for clinical application [18,19]. Antiangiogenic gene therapy can overcome these problems and represents a promising new approach for the treatment of cancer. Gene therapy using a recombinant adenovirus (Ad) encoding secretory human endostatin (Ad-Endo) has been demonstrated to be a promising antiangiogenesis and antitumor strategy of in animal models and clinical trials. We aimed to investigate the antitumor effects of antiangiogenic agent Ad-Endo combined with the oncolytic Ad dl1520 on gastric cancer (GC) in vitro and in vivo and determine the mechanisms of these effects
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