E1B-55kD-deleted oncolytic adenovirus armed with canstatin gene yields an enhanced anti-tumor efficacy on pancreatic cancer |
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Authors: | Xiao-Ping He Chang-Qing Su Xing-Hua Wang Xue Pan Zhen-Xing Tu Yang-Fang Gong Jun Gao Zhuan Liao Jing Jin Hong-Yu Wu Xiao-Hua Man Zhao-Shen Li |
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Affiliation: | 1. Department of Gastroenterology, Changhai Hospital, Second Military Medical University, 147 Changhai Rd., Shanghai 200433, China;2. Department of Gene and Viral Therapy, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, 225 Changhai Rd., Shanghai 200438, China;3. Department of Surgery, Changhai Hospital, Second Military Medical University, 147 Changhai Rd., Shanghai 200433, China |
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Abstract: | Conditionally-replicating adenovirus (CRAd) therapy is currently being tested against pancreatic cancer and has shown some promise. To improve the efficacy, a novel virus CRAd-Cans was designed by deletion of E1B-55 kDa gene for selective replication in tumor cells, as well as carrying a new angiogenesis inhibitor gene, canstatin. CRAd-Cans mediated higher expression of canstatin in BxPC-3 pancreatic cancer cell line compared to the replication-deficient adenovirus Ad5-Cans. The modified CRAd-Cans manifested the same selective replication and cytocidal effects in pancreatic cancer cells as ONYX-015 in vitro, yet showed greater reduction of tumor growth in nude mice with markedly prolonged survival rate in vivo (P < 0.05), compared to that of either ONYX-015 or Ad5-Cans. Pathological examination revealed viral replication, decreased microvessel density and increased cancer cell apoptosis in CRAd-Cans-treated xenografts. The results suggest that the novel oncolytic virus CRAd-Cans, showing synergistic effects of oncolytic therapy and anti-angiogenesis therapy, is a new promising therapeutics for pancreatic cancer. |
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Keywords: | Ad, adenoviral vector CMV, cytomegalovirus CRAd, conditionally-replicating adenovirus PCR, polymerase chain reaction vp, viral particles wt-Ad5, adenovirus wild type 5 MOI, multiplicity of infection pfu, plaque forming unit(s) MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide TSP, tumor-specific promoter HSA, human serum albumin |
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