RNA replicons derived from poliovirus are directly oncolytic for human tumor cells of diverse origins

The failure and/or toxicity of conventional therapies for many types of hum an cancers underscore the need for development of safe and effective altern ative treatments. Toward this goal, we describe the direct oncolytic activi ty of RNA-based vectors derived from poliovirus, termed replicons, which ar e genetically incapable of producing infectious virus. These replicons are cytopathic in vitro for human tumor cells originating from brain, breast, l ung, ovary, and skin (melanoma). The cytopathic effects in a malignant glio ma cell line were associated with nuclear DNA condensation, indicative of c ells undergoing apoptosis. Injection of replicons into established xenograf t flank tumors in scid mice resulted in oncolytic activity and extended sur vival. Inoculation of replicons into established intracranial xenograft tum ors in scid mice resulted in tumor infection within 8 h and extended surviv al. Histological analysis revealed that replicons had infected tumor cells at the site of inoculation and, most importantly, diffused to infect tumor cells that had metastasized from the initial site of implantation. The wide spectrum of cytopathic activity for human tumors combined with effective d istribution after in vivo inoculation establishes the therapeutic potential of poliovirus replicons for a variety of cancers.