Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy
Novel immunocompetent murine tumor models for the assessment of replication-competent oncolytic adenovirus efficacy
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DOI：
10.1016/s1525-0016(03)00199-0
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发表时间：
2003-09-01
影响因子：
12.4
通讯作者：
Kirn, D
中科院分区：
文献类型：
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作者：
Halldén, G;Hill, R;Kirn, D
溶瘤复制选择性腺病毒构成了治疗癌症的快速扩展的实验方法。然而，由于缺乏免疫活性和复制活性的功效模型，宿主免疫应答和病毒B免疫调节基因的作用仍然未知。我们筛选了9个小鼠肿瘤细胞系的腺病毒（Ads）摄取，基因表达，复制和细胞病变的影响。在这些鼠细胞系的感染性和细胞病变的影响是类似的人癌细胞系。令人惊讶的是，在几个细胞系中证实了有效的病毒复制;复制的水平与一些人癌细胞系（例如，CMT-64）降至极低水平。这些细胞系中的7个作为皮下异种移植物在免疫活性小鼠中生长，随后直接注射Ads、盐水或复制缺陷型对照腺病毒颗粒，以评估瘤内病毒基因表达、复制和抗肿瘤作用。E1 A、外壳蛋白表达和细胞病变效应在5种异种移植物中记录;在CMT-64和JC异种移植物中证明了广告复制。与盐水和非复制对照Ad颗粒相比，Ad在复制允许的异种移植物（CMT-64，JC）和弱允许的肿瘤（CMT-93）中均表现出显著的功效;与无胸腺小鼠相比，在免疫活性小鼠中对CMT-93肿瘤的功效显著更大。这些小鼠肿瘤异种移植模型具有阐明溶瘤腺病毒抗肿瘤作用中涉及的病毒和宿主免疫机制的潜力。
Oncolytic replication-selective adenoviruses constitute a rapidly expanding experimental approach to the treatment of cancer. However, due to the lack of an immunocompetent and replication-competent efficacy model, the role of the host immune response and viral B immunoregulatory genes remained unknown. We screened nine murine carcinoma lines for adenovirus (Ads) uptake, gene expression, replication, and cytopathic effects. In seven of these murine cell lines the infectability and cytopathic effects were similar to those seen with human carcinoma lines. Surprisingly, productive viral replication was demonstrated in several lines; replication varied from levels similar to those for some human carcinoma lines (e.g., CMT-64) to very low levels. Seven of these lines were grown as subcutaneous xenografts in immunocompetent mice and were subsequently injected directly with Ads, saline, or a replication-deficient control adenovirus particle to assess intratumoral viral gene expression, replication, and antitumoral effects. E1A, coat protein expression, and cytopathic effects were documented in five xenografts; Ads replication was demonstrated in CMT-64 and JC xenografts. Ads demonstrated significant efficacy compared to saline and nonreplicating control Ad particles in both replication-permissive xenografts (CMT-64, JC) and poorly permissive tumors (CMT-93); efficacy against CMT-93 tumors was significantly greater in immunocompetent mice compared to athymic mice. These murine tumor xenograft models have potential for elucidating viral and host immune mechanisms involved in oncolytic adenovirus antitumoral effects.