Antitumor efficacy of a recombinant adenovirus encoding endostatin combined with an E1B55KD-deficient adenovirus in gastric cancer cells

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.

ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib

“…The data were evaluated using ANOVA with SPSS16.0 software. The combined effect of the drugs was assessed with the Q value using Zheng-Jun Jin's method as previously described [ 42 - 44 ]: Q = E AB /[E A +E B (1-E A )] (E A , E B and E AB indicate the inhibitory rates of A, B and the combination of the two drugs). The effect of the combination of two drugs can be classified as antagonistic (Q < 0.85), additive (0.85 < Q < 1.15), or synergistic (Q>1.15).…”

Role of Recombinant DNA Technology to Improve Life

“…In a similar way, tumor growth was inhibited by adenoviral vector that encodes endostain human secretory form through antiangiogenic effects. Antiangiogenic effect can be enhanced by dl 1520 through rescuing replication of Ad-Endo [14]. Targeted gene disruption has been used to produce antitumor derivatives in other hosts which were structurally similar for the production pathways [15].…”

Recent advances in oncolytic adenovirus therapies for cancer

“…These Ad-Endo trials resulted in one objective response in a patient with nasopharyngeal carcinoma, 12 patients had stable disease, and two had disease progression [24] [25]. Ad-Endo has been used in combination with an Onc.Ad to amplify the endostatin expression in murine xenograft models, and this combination demonstrated more potent anti-tumor and antiangiogenic effects than treatments of either agent alone [26]. …”