Second-generation replication-competent oncolytic adenovirus armed with improved suicide genes and ADP gene demonstrates greater efficacy without increased toxicity
Second-generation replication-competent oncolytic adenovirus armed with improved suicide genes and ADP gene demonstrates greater efficacy without increased toxicity
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DOI：
10.1016/j.ymthe.2005.10.005
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发表时间：
2006-02-01
影响因子：
12.4
通讯作者：
Freytag, SO
中科院分区：
文献类型：
--
作者：
Barton, KN;Paielli, D;Freytag, SO
复制型腺病毒介导的自杀基因治疗已被证明是安全的，在人类前列腺内交付。虽然疗效的迹象正在出现，但在这项技术在临床上广泛应用之前，可能还需要进一步的改进。为此，我们已经开发了第二代具有复制能力的腺病毒（Ad 5 yCD/mutTK-（SR 39）rep-ADP），其含有改进的酵母胞嘧啶脱氨酶（YCD）/突变体（SR 39）单纯疱疹病毒胸苷激酶融合体（yCD/mutTK（SR 39））基因和腺病毒死亡蛋白（ADP）基因。相对于第一代Ad 5-CD/TKrep腺病毒，Ad 5-yCD/mutTK（SR 39）rep-ADP在体外表现出更大的肿瘤细胞杀伤，并且在人类癌症的临床前模型中表现出显著更大的肿瘤控制。将fadenovirus直接注射到人肿瘤异种移植物和幼稚犬前列腺中后转基因体积的定量表明ADP增强了腺病毒在体内的传播。进行毒理学研究以确定改进的yCD/mutTKSR 39融合和ADP基因是否增加毒性。前列腺内注射Ad 5 yCD/mutTK（SR 39）rep-ADP相对于亲本Ad 5CD/TKrep腺病毒没有导致显著增加的毒性，后者在两个I期前列腺癌临床试验中被证明是安全的。总之，这些结果为评价第二代Ad 5-yCD/mutTKSR 39 rep-ADP腺病毒在人体中的安全性和有效性提供了科学依据。
Replication-competent adenovirus-mediated suicide gene therapy has proven to be safe in humans when delivered intraprostatically. Although signs of efficacy are emerging, it is likely that further improvements will be needed before this technology will have widespread applicability in the clinic. Toward this end, we have developed a second-generation, replication -competent adenovirus (Ad5yCD/mutTK-(SR39)rep-ADP) containing an improved yeast cytosine deaminase (YCD)/mutant(SR39) herpes simplex virus thymidine kinase fusion (yCD/mutTK(SR39)) gene and the adenovirus death protein (ADP) gene. Relative to the first-generation Ad5-CD/TKrep adenovirus, Ad5-yCD/mutTK(SR39)rep-ADP demonstrated greater tumor cell kill in vitro and significantly greater tumor control in preclinical models of human cancer. Quantification of transgene volume following direct injection of fadenovirus into human tumor xenografts and the naive canine prostate demonstrated that ADP enhanced adenoviral spread in vivo. Toxicology studies were performed to determine whether the improved yCD/mutTKSR39 fusion and ADP genes increased toxicity. Intraprostatic injection of Ad5yCD/mutTK(SR39)rep-ADP did not result in significantly increased toxicity relative to the parental Ad5CD/TKrep adenovirus, the latter of which has proven to be safe in two Phase I prostate cancer clinical trials. Together, these results provide the scientific basis for evaluating the safety and efficacy of the second-generation Ad5-yCD/mutTKSR39rep-ADP adenovirus in humans.