In order to overcome difficulties that hampered widespread application of antiangiogenesis in cancer therapy, a highly specific delivery system may be engaged in vivo to deliver and express antiangiogenic genes. We selected a strain of Bifidobacterium adolescentis ( B. adolescentis ) as the delivery system to transport endostatin gene to solid tumors. B. adolescentis with endostatin gene were injected into tumor -bearing mice through the tail vein. After the mice were sacrificed, the tumor and some normal tissues of the mice were examined. B. adolescentis were only found in the tumors and no bacilli were found in other normal tissues. Also, a strong inhibition of angiogenesis had been shown to inhibit local tumor growth in the administrated group. These results suggested that B. adolescentis only germinated and proliferated in solid tumors and might be a highly specific and efficient vector for transporting anticancer genes into target tumor in cancer gene therapy.
To overcome difficulties that hampered widespread application of a specific delivery system in cancer gene therapy and to inhibit the growth of solid liver cancer, we utilized a strain of Bifidobacterium longum as a delivery system to transport an endostatin gene that can inhibit growth of tumor. The B. longum strain with the endostatin gene (B. longum-En) was taken orally by tumor-bearing nude mice through drencher preparation. The results showed that B. longum-En could strongly inhibit the growth of solid liver tumor in nude mice and prolong the survival time of tumor-bearing nude mice. Furthermore, tumor growth was inhibited more efficiently when the B. longum-En treatment included selenium. Enriching the B. longum-En treatment with selenium improves the activity of NK and T cells and stimulates the activity of IL-2 and TNF-alpha in BALB/c mice. These results suggest that B. longum may be a highly specific and efficient vector for transporting anticancer genes in cancer gene therapy.
Bcl-2 is an anti-apoptotic protein. If the level of Bcl-2 protein can be reduced sufficiently in tumors using RNA interference (RNAi) to target the gene message, the apoptosis of tumor cells may be promoted. In this study, we synthesized 19 nucleotides (nts) small interference RNA (siRNA) constructs suppressing bcl-2 gene expression in human tumor cells (HeLaB2 and BGC-823 cell lines) in vitro. The bcl-2 gene expression levels were significantly reduced when these siRNA were transfected into experimental two tumor cells for 72 hours. The apoptosis process was also examined in the tumor cells. Here we synthesized siRNA from a DNA template under the control of the RNA polymerase III promoter in transfected tumor cells. Using this DNA vector-based approach, we found that the siRNA efficiently and specifically inhibited the synthesis of protein encoded by the bcl-2 gene in HeLaB2 and BGC-823 tumor cells. Tumor growth was inhibited by 66.5% with 2mg/kg pSilencer 3.1H1-bcl-2 in mouse liver tumor-bearing BALB/c mice. This approach may prove to be a valuable clinical technique for the analysis of specific gene functions and gene therapy of malignant tumors that utilize the bcl-2 gene via RNA interference.
Bifidobacterium longum (B. longum) as a delivery system for endostatin was shown to have definite antitumor effects. Moreover, it was found that the enrichment of sele-nium was able to enhance the immunity of mice. In order to further evaluate the safety and efficacy of B. longum carrying pBV22210-endostatin (B. longum-En) enriched with selenium (Se-B. longum-En), we determined the biochemical characteristics of Se-B. longum-en. We then investigated its effect on macrophage activity, as well as its inhibitory effect on the multiplication of pathogenic bacteria in vitro and the anti-tumor effects on murine hepatic (H22) tumor-bearing mice. The results showed that Se-B. longum-En exhibited similar biochemical characteristics to that of wild-type B. longum, i.e., Se-B. longum-en strongly enhanced macrophage phago-cytosis in rats and inhibited the growth of pathogenic bacteria. in addition, Se-B. longum-En showed a definite inhibitory effect of tumor growth when H22 tumor-bearing mice were fed through oral or tail vein delivery. These results suggested that Se-B. longum is able to retain the advantages of wild-type B. longum and be used as a novel gene delivery system for liver cancer gene therapy.
Endostatin gene could be efficiently transported into the mice with TF-liposome-DNA delivery system by administration of aerosol. TF-liposome-mediated endostatin gene therapy strongly inhibited angiogenesis and the growth of mouse xenograft liver tumors. It also could promote the development of apoptosis of tumors without direct influence on tumor cells.
Abstract. Small interfering RNAs (siRNAs) are valuable reagents for efficient gene silencing in a sequence-specific manner via the RNA interference (RNAi) pathway. The current synthetic siRNA structure consists of symmetrical duplexes of 19-21 base pairs (bp) with 2 nucleotide (nt) 3' overhangs. In this study, we report that an asymmetric siRNA (asiRNA) consisting of 17 bp duplex region (17 bp asiRNA) exhibited potent activity in inhibiting bcl-2 gene expression and cancer cell proliferation in vitro. Importantly, this asiRNA structure significantly reduced off-target silencing by the sense strand. To improve the stability of the 17 bp asiRNA, we synthesized a series of chemically modified 17 bp asiRNAs. Further experiments showed that in comparison with the 17 bp asiRNA, the 17 bp asiRNA-M2, one of the modified 17 bp asiRNAs, exhibited a comparable gene silencing activity and an improved stability in vitro. Furthermore, the 17 bp asiRNA-M2 with a proteolipid micelle delivery system can effectively suppress the growth of H22 and BGC 803 tumors in vivo. These results suggest that the chemically modified asiRNAs may have potential as an effective therapeutic approach for cancer gene therapy in the future.
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