1. ¹Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
2. ²Department of Neurological Surgery, University of Southern California, Los Angeles, CA 90033, USA

Correspondence: Noriyuki Kasahara, UCLA Geffen School of Medicine, MRL-1551, 675 Charles E. Young Drive South, Los Angeles, CA 90095, USA. Fax: +1 310 825 5204. E-mail: nkasahara@mednet.ucla.edu

Received 17 February 2005; Accepted 17 March 2005.

Abstract

Achieving therapeutically efficacious levels of gene transfer in tumors has been a major obstacle for cancer gene therapy using replication-defective virus vectors. Recently, replicating viruses have emerged as attractive tools for cancer therapy, but generally achieve only transitory tumor regression. In contrast to other replicating virus systems, transduction by replication-competent retrovirus (RCR) vectors is efficient, tumor-selective, and persistent. Correlating with its efficient replicative spread, RCR vector expressing the yeast cytosine deaminase suicide gene exhibited remarkably enhanced cytotoxicity in vitro after administration of the prodrug 5-fluorocytosine. In vivo, RCR vectors replicated throughout preestablished primary gliomas without spread to adjacent normal brain, resulting in profound tumor inhibition after a single injection of virus and single cycle of prodrug administration. Furthermore, stable integration of the replicating vector resulted in persistent infection that achieved complete transduction of ectopic glioma foci that had migrated away from the primary tumor site. Thus, efficient and stable integration of suicide genes represents a unique property of the RCR vector that achieved multiple cycles of synchronous cell killing upon repeated prodrug administration, resulting in chronic suppression of tumor growth and prolonged survival.