ORIGINAL ARTICLE Regional administration of oncolytic Echovirus 1 as a novel therapy for the peritoneal dissemination of gastric cancer Erin S. Haley & Gough G. Au & Brian R. Carlton & Richard D. Barry & Darren R. Shafren Received: 10 September 2008 / Revised: 27 November 2008 / Accepted: 3 December 2008 / Published online: 13 January 2009 # Springer-Verlag 2008 Abstract The dissemination of malignant gastric cells to the peritoneum occurs frequently, usually as an early event in disease, and results in poor patient prognosis. Surgery and chemotherapy offer limited therapeutic success. The low-pathogenic human enterovirus, Echovirus 1 (EV1), is an oncolytic virus that selectively targets and destroys malignant prostate and ovarian cancer xenografts in vivo. Lytic EV1 infection requires the cell surface expression of α 2 β 1 , an integrin involved in the dissemination of gastric cancer cells to the peritoneum. Herein, we evaluated the capacity of EV1 for anti-neoplastic cell action in gastric peritoneal carcinomatosis. Flow cytometric analysis dem- onstrated that α 2 β 1 was abundantly surface expressed on a panel of gastric cancer cell lines, rendering the majority of lines highly susceptible to in vitro lytic EV1 infection and supportive of efficient viral progeny production. A biolu- minescent MKN-45-Luc SCID mouse model of peritoneal dissemination was developed to allow real-time non- invasive monitoring of peritoneal tumor burden. Employing this mouse model, we demonstrated a therapeutic dose- response for escalating oncolytic EV1 doses. Taken together, these results emphasize the exciting potential for EV1 as a single or adjunct therapy for the control of the peritoneal dissemination of gastric cancer. Keywords Echovirus 1 . Oncolytic virus . Virotherapy . Gastric cancer . Peritoneal dissemination Introduction Gastric cancer is the fourth most common type of cancer and the second most common cause of cancer-related mortalities worldwide. Almost two thirds of cases occur in the developing world [1]. In the United States and Europe, the 5-year survival rate is less than 20% as detection usually occurs in the late stage of disease [2]. Peritoneal carcinomatosis (PC) or dissemination in gastric cancer occurs frequently and early, with PC staging usually advanced at diagnosis of the primary cancer. The median survival for patients with PC is 3.1 months [3]. In the absence of early carcinomatosis in gastric cancer patients, the peritoneum is the most common site of recurrence following surgical resection of primary lesions [4]. Traditionally, the survival advantage offered by surgery or systemic chemotherapy for disseminated peritoneal disease is limited [5, 6]. Recent studies have demonstrated some success with cytoreductive surgery for the removal of macroscopic lesions, in combination with intraoperative peritoneal hyperthermic chemotherapy for the elimination of micrometastases and free cancer cells [7]. Regardless, the inherent toxicities associated with chemotherapy sug- gest that investigation of novel therapies for PC is warranted. An innovative potential anti-neoplastic strategy for the treatment of PC is oncolytic virotherapy, which involves the use of either genetically engineered or naturally occurring J Mol Med (2009) 87:385–399 DOI 10.1007/s00109-008-0433-0 E. S. Haley : G. G. Au : R. D. Barry : D. R. Shafren (*) The Picornavirus Research Unit, School of Biomedical Sciences, Faculty of Health, The University of Newcastle, Newcastle, NSW 2300, Australia e-mail: dshafren@mail.newcastle.edu.au B. R. Carlton Animal Services Unit, The University of Newcastle, Newcastle, NSW 2300, Australia D. R. Shafren Viralytics Ltd, Unit 8, 33 Ryde Road, Pymble, NSW 2073, Australia