Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus
Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus
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DOI：
10.1016/s1525-0016(03)00200-4
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发表时间：
2003-09-01
影响因子：
12.4
通讯作者：
Hemminki, A
中科院分区：
文献类型：
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作者：
Kanerva, A;Zinn, KR;Hemminki, A
溶瘤病毒在肿瘤中具有复制能力，但在正常细胞中不具有复制能力，代表了治疗肿瘤性疾病的新方法。然而，复制剂的溶瘤效力直接由其感染靶细胞的能力决定。用于基因治疗或病毒治疗的大多数腺病毒都是基于血清型5（Ad 5）。不幸的是，Ad 5的主要受体（柯萨奇-腺病毒受体，或CAR）在卵巢癌和其他癌细胞中的表达是高度可变的。通过进行遗传纤维假型化，我们创建了Ad 5/3-Delta 24，这是一种条件复制型腺病毒，不结合CAR，但有助于进入和杀死卵巢癌细胞。我们显示了Ad 5/3-Delta 24的复制和随后的卵巢腺癌细胞系的溶瘤作用。还用定量PCR对从患者样品中纯化的三维原发性肿瘤细胞球状体进行复制分析。此外，在腹膜癌转移的原位治疗模型中，观察到显著提高的存活率。最后，Ad 5/3-Delta 24通过非侵入性体内生物发光成像评估实现了显著的抗肿瘤效果。因此，Ad 5/3-Delta 24的临床前治疗功效相对于各自的CAR和整联蛋白结合对照得到改善。结合有希望的生物分布和毒性数据，这种方法可以转化为卵巢癌患者的成功临床干预。
Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.