Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
Viruses. 2023 Jun 29;15(7):1472. doi: 10.3390/v15071472.
Patients with stage IV gastric cancer suffer from dismal outcomes, a challenge especially in many Asian populations and for which new therapeutic options are needed. To explore this issue, we used oncolytic reovirus in combination with currently used chemotherapeutic drugs (irinotecan, paclitaxel, and docetaxel) for the treatment of gastric and other gastrointestinal cancer cells in vitro and in a mouse model. Cell viability in vitro was quantified by WST-1 assays in human cancer cell lines treated with reovirus and/or chemotherapeutic agents. The expression of reovirus protein and caspase activity was determined by flow cytometry. For in vivo studies, athymic mice received intratumoral injections of reovirus in combination with irinotecan or paclitaxel, after which tumor size was monitored. In contrast to expectations, we found that reoviral oncolysis was only poorly correlated with Ras pathway activation. Even so, the combination of reovirus with chemotherapeutic agents showed synergistic cytopathic effects in vitro, plus enhanced reovirus replication and apoptosis. In vivo experiments showed that reovirus alone can reduce tumor size and that the combination of reovirus with chemotherapeutic agents enhances this effect. Thus, we find that oncolytic reovirus therapy is effective against gastric cancer. Moreover, the combination of reovirus and chemotherapeutic agents synergistically enhanced cytotoxicity in human gastric cancer cell lines in vitro and in vivo. Our data support the use of reovirus in combination with chemotherapy in further clinical trials, and highlight the need for better biomarkers for reoviral oncolytic responsiveness.
患有 IV 期胃癌的患者预后较差，这是一个挑战，尤其是在许多亚洲人群中，他们需要新的治疗选择。为了探索这个问题，我们使用溶瘤呼肠孤病毒联合目前使用的化疗药物（伊立替康、紫杉醇和多西他赛）治疗体外和小鼠模型中的胃癌和其他胃肠道癌细胞。用溶瘤呼肠孤病毒和/或化疗药物处理人癌细胞系后，通过 WST-1 测定法定量测定细胞活力。通过流式细胞术确定呼肠孤病毒蛋白的表达和半胱天冬酶活性。在体内研究中，荷瘤小鼠接受溶瘤呼肠孤病毒联合伊立替康或紫杉醇的瘤内注射，然后监测肿瘤大小。出乎意料的是，我们发现呼肠孤病毒溶瘤作用与 Ras 通路激活仅呈低度相关。即便如此，呼肠孤病毒与化疗药物的联合使用在体外显示出协同的细胞病变效应，以及增强的呼肠孤病毒复制和细胞凋亡。体内实验表明，呼肠孤病毒单独就能缩小肿瘤大小，而呼肠孤病毒与化疗药物的联合使用则增强了这种效果。因此，我们发现溶瘤呼肠孤病毒治疗对胃癌有效。此外，呼肠孤病毒与化疗药物联合使用在体外和体内均协同增强了人胃癌细胞系的细胞毒性。我们的数据支持在进一步的临床试验中使用呼肠孤病毒联合化疗，并强调需要更好的生物标志物来预测呼肠孤病毒的溶瘤反应性。
