Hirasawa Kensuke, Nishikawa Sandra G, Norman Kara L, Coffey Matthew C, Thompson Bradley G, Yoon Chang-Soon, Waisman David M, Lee Patrick W K
Cancer Biology Research Group and Departments of Microbiology and Infectious Diseases, University of Calgary, School of Medicine, Calgary, Alberta, T2N 4N1 Canada.
Cancer Res. 2003 Jan 15;63(2):348-53.
The human reovirus is an oncolytic virus that specifically targets cancer cells with an activated Ras pathway. Because it is replication competent and highly specific for cancer cells, this virus has the potential to be an effective antimetastatic cancer agent through remote site delivery. In this study, we exploited the ability of reovirus to replicate in murine cells to test the efficacy of this virus in eliminating distal and/or metastatic tumors in immune-competent mice. We found that i.v. therapy with reovirus not only inhibited metastatic tumor growth but also led to a significant improvement in animal survival. Combining i.v. reovirus treatment with immune suppression (cyclosporine A or anti-CD4/anti-CD8 antibodies) resulted in further reduction in tumor size and a considerable prolongation in survival, compared with viral therapy alone. Combined therapy was also effective in overcoming a preexisting immunity to reovirus (a common occurrence in humans and thus a potential impediment to oncolytic effectiveness) to induce metastatic tumor regression. This is the first study to use systemic delivery of an oncolytic agent in conjunction with immune-suppressive drugs to effectively prolong animal survival. Altogether, our results suggest that i.v. reovirus therapy may present a feasible, novel alternative in the treatment of metastatic cancer in humans.
人呼肠孤病毒是一种溶瘤病毒，它特异性靶向具有激活的Ras信号通路的癌细胞。由于它具有复制能力且对癌细胞具有高度特异性，这种病毒有可能通过远程递送成为一种有效的抗转移性癌症药物。在本研究中，我们利用呼肠孤病毒在鼠细胞中复制的能力，来测试这种病毒在消除免疫健全小鼠的远端和/或转移性肿瘤方面的疗效。我们发现，静脉注射呼肠孤病毒疗法不仅抑制转移性肿瘤生长，还显著提高了动物存活率。与单独的病毒疗法相比，将静脉注射呼肠孤病毒治疗与免疫抑制（环孢素A或抗CD4/抗CD8抗体）相结合，导致肿瘤大小进一步减小，存活期显著延长。联合疗法在克服对呼肠孤病毒的预先存在的免疫力（在人类中常见，因此是溶瘤有效性的潜在障碍）以诱导转移性肿瘤消退方面也有效。这是第一项使用溶瘤剂全身递送并结合免疫抑制药物来有效延长动物存活期的研究。总之，我们的结果表明，静脉注射呼肠孤病毒疗法可能为人类转移性癌症的治疗提供一种可行的新选择。
