1. ¹Molecular Medicine Program and Virology and Gene Therapy Track, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
2. ²Southern Research Institute, Birmingham, Alabama, USA
3. ³University of Alabama at Birmingham, Birmingham, Alabama, USA

Correspondence: Roberto Cattaneo, Mayo Clinic Rochester, Molecular Medicine Program, Guggenheim 1838, 200 First Street SW, Rochester, Minnesota, 55902, USA. E-mail: cattaneo.roberto@mayo.edu

^*Present address: Department of Gastroenterology, University Hospital Heidelberg, Infectious Diseases and Intoxications, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

Received 13 April 2007; Accepted 25 July 2007; Published online 21 August 2007.

Abstract

An immunocompetent model is required to test therapeutic regimens for clinical trials with the oncolytic measles virus (MV). Toward developing this model, a retargeted MV that enters murine colon adenocarcinoma cells forming tumors in syngeneic C57BL/6 mice was generated. Since MV infection tends to be less efficient in murine than in human cells, the targeted virus was also armed with the prodrug convertase, purine nucleoside phosphorylase (PNP), and named MV-PNP-antiCEA. We have shown before that in cultured cells, infection with this virus activated the prodrug, 6-methylpurine-2'-deoxyriboside (MeP-dR), causing extensive cytotoxicity. When injected intratumorally (IT), MV-PNP-antiCEA inhibited subcutaneous tumor growth marginally, but subsequent administration of the prodrug enhanced the oncolytic effect. Systemic delivery of MV-PNP-antiCEA alone had no substantial oncolytic effects, but in combination with the prodrug it was therapeutic, revealing synergistic effects between virus and prodrug. Immunosuppression with cyclophosphamide (CPA) retarded the appearance of MV neutralizing antibodies and enhanced oncolytic efficacy: survival was 100%, with 9 out of 10 animals going into complete remission. This immunocompetent murine model facilitates the testing of therapeutic regimens for clinical trials.