Lam John T, Kanerva Anna, Bauerschmitz Gerd J, Takayama Koichi, Suzuki Kaori, Yamamoto Masato, Bhoola Snehal M, Liu Bin, Wang Minghui, Barnes Mack N, Alvarez Ronald D, Siegal Gene P, Curiel David T, Hemminki Akseli
Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Gene Med. 2004 Dec;6(12):1333-42. doi: 10.1002/jgm.635.
Gene therapy offers a new strategy for cancer treatment. Adenoviruses represent the most widely used gene therapy vector and feature an excellent safety record. Conditionally replicative adenoviruses (CRAds) effect solid tumor penetration and tumor selective oncolysis and consequently offer potential efficacy for metastatic disease treatment. We evaluated five CRAds as candidate clinical agents for ovarian cancer therapy: RGDCRADcox-2R, Ad5VEGFE1, Ad5/3VEGFE1, Ad5-Delta24RGD, and Ad5/3-Delta24.
DNA replication by these five CRAds, wild-type adenovirus, and an E1-deleted control was measured in purified primary ovarian cancer cell spheroids by quantitative PCR. CRAd-mediated oncolysis was quantified in ovarian cancer cell monolayers and three-dimensional spheroids by cellular viability assays. The therapeutic efficacy of each CRAd was tested by intraperitoneal administration in mice with peritoneally disseminated human ovarian cancer.
An increase in viral DNA was noted in primary tumor cell spheroids for all replicative viruses tested. Variation was noted in viral DNA replication between patient samples. All five CRAds induced remarkable oncolysis. They also prolonged survival in vivo compared with the wild-type control group.
All five CRAds tested showed robust DNA replication, oncolysis, and in vivo therapeutic efficacy. Each virus has potential for clinical testing, and such further testing will ultimately determine its safety and relative usefulness. Variation of CRAd DNA replication between different patient samples suggests that target tissue features, such as surface receptors and endogenous transcription factors, may affect CRAd infectivity and replicativity. Evaluation of such factors may become important to optimize cancer therapy for individual patients.
基因治疗为癌症治疗提供了一种新策略。腺病毒是最广泛使用的基因治疗载体，具有出色的安全记录。条件性复制腺病毒（CRAds）可实现实体瘤穿透和肿瘤选择性溶瘤，因此对转移性疾病治疗具有潜在疗效。我们评估了五种CRAds作为卵巢癌治疗的候选临床药物：RGDCRADcox-2R、Ad5VEGFE1、Ad5/3VEGFE1、Ad5-Delta24RGD和Ad5/3-Delta24。
通过定量PCR在纯化的原发性卵巢癌细胞球体中测量这五种CRAds、野生型腺病毒和E1缺失对照的DNA复制。通过细胞活力测定在卵巢癌细胞单层和三维球体中对CRAd介导的溶瘤进行定量。通过对腹膜播散性人卵巢癌小鼠进行腹腔给药来测试每种CRAds的治疗效果。
在所测试的所有复制病毒的原发性肿瘤细胞球体中均观察到病毒DNA增加。患者样本之间的病毒DNA复制存在差异。所有五种CRAds均诱导了显著的溶瘤作用。与野生型对照组相比，它们还延长了体内生存期。
所测试的所有五种CRAds均显示出强大的DNA复制、溶瘤作用和体内治疗效果。每种病毒都有进行临床试验的潜力，而这种进一步的测试最终将确定其安全性和相对效用。不同患者样本之间CRAd DNA复制的差异表明，诸如表面受体和内源性转录因子等靶组织特征可能会影响CRAd的感染性和复制性。评估这些因素对于优化个体患者的癌症治疗可能变得很重要。
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