Hirasawa Kensuke, Nishikawa Sandra G, Norman Kara L, Alain Tommy, Kossakowska Anna, Lee Patrick W K
Cancer Biology Research Group and Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, T2N 4N1 Canada.
Cancer Res. 2002 Mar 15;62(6):1696-701.
Reovirus selectively replicates in and destroys cancer cells with an activated Ras signaling pathway. In this study, we evaluated the feasibility of using reovirus (serotype 3, strain Dearing) as an antihuman colon and ovarian cancer agent. In in vitro studies, reovirus infection in human colon and ovarian cell lines was assessed by cytopathic effect as detected by light microscopy, [(35)S]Methionine labeling of infected cells for viral protein synthesis and progeny virus production by plaque assay. We observed that reovirus efficiently infected all five human colon cancer cell lines (Caco-2, DLD-1, HCT-116, HT-29, and SW48) and four human ovarian cancer cell lines (MDAH2774, PA-1, SKOV3, and SW626) which were tested, but not a normal colon cell line (CCD-18Co) or a normal ovarian cell line (NOV-31). We also observed that the Ras activity in the human colon and ovarian cancer cell lines was elevated compared with that in normal colon and ovarian cell lines. In animal models, intraneoplastic as well as i.v. inoculation of reovirus resulted in significant regression of established s.c. human colon and ovarian tumors implanted at the hind flank. Histological studies revealed that reovirus infection in vivo was restricted to tumor cells, whereas the surrounding normal tissue remained uninfected. Additionally, in an i.p. human ovarian cancer xenograft model, inhibition of ascites tumor formation and the survival of animals treated with live reovirus was significantly greater than of control mice treated with UV-inactivated reovirus. Reovirus infection in ex vivo primary human ovarian tumor surgical samples was also confirmed, further demonstrating the potential of reovirus therapy. These results suggest that reovirus holds promise as a novel agent for human colon and ovarian cancer therapy.
呼肠孤病毒选择性地在具有激活的Ras信号通路的癌细胞中复制并将其破坏。在本研究中，我们评估了使用呼肠孤病毒（3型，Dearing株）作为抗人结肠癌和卵巢癌药物的可行性。在体外研究中，通过光学显微镜检测细胞病变效应来评估呼肠孤病毒在人结肠和卵巢细胞系中的感染情况，用[³⁵S]甲硫氨酸标记感染细胞以检测病毒蛋白合成，并通过蚀斑试验检测子代病毒产生。我们观察到，呼肠孤病毒能有效感染所检测的全部5种人结肠癌细胞系（Caco-2、DLD-1、HCT-116、HT-29和SW48）以及4种人卵巢癌细胞系（MDAH2774、PA-1、SKOV3和SW626），但不能感染正常结肠细胞系（CCD-18Co）或正常卵巢细胞系（NOV-31）。我们还观察到，与正常结肠和卵巢细胞系相比，人结肠和卵巢癌细胞系中的Ras活性有所升高。在动物模型中，瘤内以及静脉注射呼肠孤病毒均导致在后侧腹植入的已形成的人结肠和卵巢皮下肿瘤显著消退。组织学研究显示，呼肠孤病毒在体内的感染仅限于肿瘤细胞，而周围正常组织未被感染。此外，在腹腔内人卵巢癌异种移植模型中，活呼肠孤病毒治疗的动物腹水肿瘤形成的抑制作用及生存率显著高于经紫外线灭活的呼肠孤病毒治疗的对照小鼠。体外人卵巢原发性肿瘤手术样本中的呼肠孤病毒感染也得到了证实，进一步证明了呼肠孤病毒治疗的潜力。这些结果表明，呼肠孤病毒有望成为治疗人结肠癌和卵巢癌的新型药物。
