Intravesical Ad-IFNα causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-α protein
Intravesical Ad-IFNα causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-α protein
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DOI：
10.1016/j.ymthe.2004.05.027
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发表时间：
2004-09-01
影响因子：
12.4
通讯作者：
Connor, RJ
中科院分区：
文献类型：
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作者：
Benedict, WF;Tao, ZM;Connor, RJ
我们通过膀胱内滴注编码干扰素-α的腺病毒（Ad-IFN α）和基因转移剂Syn 3，在体内产生了长时间的高局部浓度干扰素。我们发现持续干扰素蛋白水平的天，无论是在正常小鼠尿路上皮和人膀胱癌细胞生长的浅表性膀胱肿瘤裸鼠使用原位膀胱模型，我们开发的。利用含有绿色荧光蛋白的癌细胞测定膀胱中的肿瘤负荷。在两次1小时的Ad-IFN α/Syn 3暴露后观察到显著的肿瘤消退，并且在正常细胞中检测到很少或没有细胞毒性。类似的膀胱内滴注单独的临床相关浓度的IFN蛋白或没有Syn 3的Ad-IFN α是无效的。令人惊讶的是，在体外，Ad-IFNalpha还引起对高浓度IFNalpha蛋白具有抗性的膀胱癌细胞系（包括体内使用的细胞系）的半胱天冬酶依赖性死亡。这些结果表明，Ad-IFN α可以克服抵抗IFN α蛋白在体外和体内，并支持膀胱内的Ad-IFN α/Syn 3治疗浅表性膀胱癌的评价。
We have produced prolonged, high local concentrations of interferon in vivo by intravesical instillation of adenoviruses encoding interferon-alpha, (Ad-IFNalpha) together with the gene transferenhancing agent Syn3. We found sustained interferon protein levels for days, both in normal mouse urotheliurn and in human bladder cancer cells growing as superficial bladder tumors in nude mice using an orthotopic bladder model developed by us. Tumor burden in the bladder was determined utilizing cancer cells containing the green fluorescent protein. Marked tumor regression was observed following two 1-h exposures of Ad-IFNalpha/Syn3 and little or no cytotoxicity was detected in normal cells. Similar intravesical instillation of clinically relevant concentrations of IFN protein alone or Ad-IFNalpha without Syn3 was ineffective. Surprisingly, in vitro, Ad-IFNalpha also caused caspase-dependent death of bladder cancer cell lines that were resistant to high concentrations of IFNalpha protein, including the cell line used in vivo. These findings demonstrate that Ad-IFNalpha can overcome resistance to IFNalpha protein both in vitro and in vivo and support evaluation of intravesical Ad-IFNalpha/Syn3 for the treatment of superficial bladder cancer.