Experimental cancer gene therapy by multiple anti-survivin hammerhead ribozymes
Qi Fei
Fudan University School of Medicine, Shanghai 200032, China
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorHongyu Zhang
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorLili Fu
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorXinlan Dai
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorBaomei Gao
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorMin Ni
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorChao Ge
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorJinjun Li
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorXia Ding
Division of Cellular Dynamics, Hefei National Laboratory, University of Science and Technology of China, Hefei 230027, China
Search for more papers by this authorYuwen Ke
Division of Cellular Dynamics, Hefei National Laboratory, University of Science and Technology of China, Hefei 230027, China
Search for more papers by this authorCorresponding Author
Xuebiao Yao
Division of Cellular Dynamics, Hefei National Laboratory, University of Science and Technology of China, Hefei 230027, China
*Corresponding authors: Jingde Zhu: Tel/Fax, 86-21-64224285; E-mail, [email protected]Xuebiao Yao: Tel/Fax, 86-551-3607141; E-mail, [email protected]Search for more papers by this authorCorresponding Author
Jingde Zhu
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
*Corresponding authors: Jingde Zhu: Tel/Fax, 86-21-64224285; E-mail, [email protected]Xuebiao Yao: Tel/Fax, 86-551-3607141; E-mail, [email protected]Search for more papers by this authorQi Fei
Fudan University School of Medicine, Shanghai 200032, China
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorHongyu Zhang
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorLili Fu
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorXinlan Dai
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorBaomei Gao
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorMin Ni
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorChao Ge
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorJinjun Li
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
Search for more papers by this authorXia Ding
Division of Cellular Dynamics, Hefei National Laboratory, University of Science and Technology of China, Hefei 230027, China
Search for more papers by this authorYuwen Ke
Division of Cellular Dynamics, Hefei National Laboratory, University of Science and Technology of China, Hefei 230027, China
Search for more papers by this authorCorresponding Author
Xuebiao Yao
Division of Cellular Dynamics, Hefei National Laboratory, University of Science and Technology of China, Hefei 230027, China
*Corresponding authors: Jingde Zhu: Tel/Fax, 86-21-64224285; E-mail, [email protected]Xuebiao Yao: Tel/Fax, 86-551-3607141; E-mail, [email protected]Search for more papers by this authorCorresponding Author
Jingde Zhu
Cancer Epigenetics and Gene Therapy Program, The State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai 200032, China
*Corresponding authors: Jingde Zhu: Tel/Fax, 86-21-64224285; E-mail, [email protected]Xuebiao Yao: Tel/Fax, 86-551-3607141; E-mail, [email protected]Search for more papers by this authorThis work was supported by the grants from the Shanghai Science Foundation (No. 07DJ14074 to JZ), the National Science Foundation (Nos. 30570850 and 10574134 to JZ), the National Natural Science Foundation of China (No. 2004CB518804 to JZ and No. 2002CB713700 to XY), the National Basic Research Program of China (Nos. 2006AA02Z320 and 2006AA02Z197 to JZ), and the European 6th Program (No. LSHB-CT-2005-019067 to JZ). XY is a GCC Eminent Scholar
Abstract
To improve the efficacy of gene therapy for cancer, we designed four hammerhead ribozyme adenoviruses (R1 to R4) targeting the exposed regions of survivin mRNA. In addition to the in vitro characterization, which included a determination of the sequence specificity of cleavage by primer extension, assays for cell proliferation and for in vivo tumor growth were used to score for ribozyme efficiency. The resulting suppression of survivin expression induced mitotic catastrophe and cell death via the caspase-3-dependent pathway. Importantly, administration of the ribozyme adenoviruses inhibited tumor growth in a hepato-cellular carcinoma xenograft mouse model. Co-expression of R1, R3 and R4 ribozymes synergistically suppressed survivin and, as this combination targets all major forms of the survivin transcripts, produced the most potent anti-cancer effects. The adenoviruses carrying the multiple hammerhead ribozymes described in this report offered a robust gene therapy strategy against cancer.
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