This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nagano, S. Articles by Boucher, Y. Search for Related Content PubMed PubMed Citation Articles by Nagano, S. Articles by Boucher, Y.

Cancer Cell Death Enhances the Penetration and Efficacy of Oncolytic Herpes Simplex Virus in Tumors

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Yves Boucher, Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114. Phone: 617-726-4082; Fax: 617-724-1819; E-mail: yves{at}steele.mgh.harvard.edu.

Key Words: Apoptosis • Oncolytic virus • Interstitial transport • Cytotoxic agent • Gene therapy

The success of tumor oncolytic virotherapy is limited by the poor penetration of virus in tumors. Interstitial collagen fibers and the narrow spacing between cancer cells are major barriers hindering the movement of large viral particles. To bypass the cellular barrier, we tested the hypothesis that the void space produced by cancer cell apoptosis enhances the initial spread and efficacy of oncolytic herpes simplex virus (HSV). In mice with mammary tumors, apoptosis was induced by doxycycline-regulated expression/activation of CD8/caspase-8, paclitaxel, or paclitaxel plus tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). In both collagen-poor and collagen-rich tumors, apoptosis or necrosis increased the initial intratumoral spread of HSV. Compared with the isolated pattern of HSV infection generally located in the center of control tumors, apoptosis induction and a single i.t. injection of virus produced an interconnected and diffuse pattern of infection, which extended from the tumor center to the periphery. This interconnected pattern of viral infection correlated with the formation of void spaces and channel-like structures in apoptosis-rich tumor areas. We also show that the i.t. injection of HSV after caspase-8 activation or paclitaxel-TRAIL pretreatment retards tumor growth, whereas HSV administration before tumor cell death induction did not improve therapeutic efficacy. Hence, our findings show that the induction of cancer cell death before the injection of oncolytic HSV enhances intratumoral virus delivery/penetration and antitumor efficacy. [Cancer Res 2008;68(10):3795–802]