Halldén Gunnel, Hill Richard, Wang Yaohe, Anand Arthi, Liu T-Chiang, Lemoine Nick R, Francis Jennelle, Hawkins Lynda, Kirn David
Viral and Genetic Therapy Program, Cancer Research U.K. Molecular Oncology Unit and Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
Mol Ther. 2003 Sep;8(3):412-24. doi: 10.1016/s1525-0016(03)00199-0.
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 E3 immunoregulatory genes remained unknown. We screened nine murine carcinoma lines for adenovirus (Ad5) 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 Ad5, 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; Ad5 replication was demonstrated in CMT-64 and JC xenografts. Ad5 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.
溶瘤性复制选择性腺病毒构成了一种迅速发展的癌症治疗实验方法。然而，由于缺乏具有免疫活性和复制活性的疗效模型，宿主免疫反应和病毒E3免疫调节基因的作用仍然未知。我们筛选了9种小鼠癌细胞系，以研究腺病毒（Ad5）的摄取、基因表达、复制和细胞病变效应。在其中7种小鼠细胞系中，其感染性和细胞病变效应与人癌细胞系相似。令人惊讶的是，在几个细胞系中证实了病毒的有效复制；复制水平从与某些人癌细胞系（如CMT-64）相似到非常低的水平不等。将其中7个细胞系作为皮下异种移植物在具有免疫活性的小鼠中培养，随后直接注射Ad5、生理盐水或复制缺陷型对照腺病毒颗粒，以评估肿瘤内病毒基因表达、复制和抗肿瘤作用。在5个异种移植物中记录了E1A、衣壳蛋白表达和细胞病变效应；在CMT-64和JC异种移植物中证实了Ad5的复制。与生理盐水和非复制对照Ad颗粒相比，Ad5在复制允许的异种移植物（CMT-64、JC）和低允许性肿瘤（CMT-93）中均显示出显著疗效；与无胸腺小鼠相比，在具有免疫活性的小鼠中，Ad5对CMT-93肿瘤的疗效显著更高。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所涉及的病毒和宿主免疫机制的潜力。
