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Wang W.,No 117 Hospital Of Chinese Pla | Ji W.,The Surgical Center | Hu H.,Fuzhou General Hospital of Nanjing Military Area | Ma J.,No 117 Hospital Of Chinese Pla | And 8 more authors.
Oncotarget | Year: 2014

Gene therapy is a promising adjuvant therapeutic strategy for cancer treatment. To overcome the limitations of current gene therapy, such as poor transfection efficiency of vectors, low levels of transgene expression and lack of tumor targeting, the Survivin promoter was used to regulate the selective replication of oncolytic adenovirus in tumor cells, and the heat shock protein 70 (Hsp70) gene was loaded as the anticancer transgene to generate an AdSurp-Hsp70 viral therapy system. The efficacy of this targeted immunotherapy was examined in gastric cancer. The experiments showed that the oncolytic adenovirus can selectively replicate in and lyse the Survivin-positive gastric cancer cells, without significant toxicity to normal cells. AdSurp-Hsp70 reduced viability of cancer cells and inhibited tumor growth of gastric cancer xenografts in immuno-deficient and immuno-reconstruction mouse models. AdSurp-Hsp70 produced dual antitumor effects due to viral replication and high Hsp70 expression. This therapeutic system used the Survivin promoter-regulated oncolytic adenovirus vector to mediate targeted expression of the Hsp70 gene and ensure safety and efficacy for subsequent gene therapy programs against a variety of cancers.

Weiqun M.,No 117 Hospital Of Chinese Pla | Xiaoya L.,The Surgical Center | Weiguo W.,No 117 Hospital Of Chinese Pla | Juming M.,No 117 Hospital Of Chinese Pla | And 5 more authors.
Chinese Journal of Cancer Biotherapy | Year: 2014

Objective: To evaluate the efficacy of cell-penetrating peptide-fused HSP70 gene therapy in combination with the use of cytokine-induced killer (CIK) cells for gastric cancer in a xenograft nude mouse model. Methods: CMV promoter-driven adenoviral vectors expressing wild-type HSP70 (AdCMV-HSP70) and HSP70 fused with a cell-penetrating peptide of 11 arginines (AdCMV-HSP70s) were constructed. In in vitro experiments, human gastric cancer SGC-7901 and GES-1 cells were infected with these two viral vectors respectively. At 48 h after infection, cell viability was assessed by MTT assays and HSP70 protein content by Western blotting. In in vivo experiments, Sgc-7901 cells were injected sub-cutaneously into BALB/c nude mice. Cancer cell-challenged mice were treated every 48 h for a total of five times with AdCMV-HSP70 or AdCMV-HSP70s, either each alone or in combination with a sing le dose of 1 × 107 CIK cells (tail vein injection) prepared from normal BALB/c mice. Thirty-five days after treatment, animals were sacrificed. The number and size of tumors formed were assessed. Results: HSP70 protein content after AdCMV-HSP70s infection was significantly higher than that after AdCMV-HSP70 infection in both SGC cells (360. 72 ±20. 89 ng/ml vs 121. 01 ± 15. 94 ng/ml, P < 0.05) and GES-1 cells (188.62 ±10.82 ng/ml vs 135.00 ±13.96 ng/ml, P<0.05). Fusion of 11 arginine peptide into HSP70 led to significant inhibition of gastric cancer cell proliferation; at low multiplicity of infection (MOI) of 100 pfu/ ml, the cell viability was (66. 33 ±4. 33)% in AdCMV-HSP70s-infected SGC-7901 cells, significantly lower than that (101. 33 ±7. 64%) in AdCMV-HSP70-infected SGC-7901 cells (P <0. 05). CIK cell administration resulted in immune reconstruction in nude mice carrying xenograft gastric cancer cells. Adenoviral delivery of HSP70 enhanced infiltration of CD3 T cells into tumor tissues and induce antitumor immune response. CIK cells in combination with AdCMV-HSP70s showed a significantly higher tumor inhibition rate (66. 5%) than CIK cells in combination with AdCMV-HSP70 (43. 6%) in nude mince challenged with gastric cancer cells (P <0. 05). Conclusion: In nude mice carrying human gastric cancer cells, HSP70 may not only inhibit gastric cancer cell proliferation but also induce antitumor immune response. These effects can be enhanced by fusion of a cell-penetrating peptide with the HSP70 molecule and implantation of cytokine-induced killer cells.

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