Improved Killing of Human High-Grade Glioma Cells by Combining Ionizing Radiation with Oncolytic Parvovirus H-1 Infection

Abstract EN

Purpose.

To elucidate the influence of ionizing radiation (IR) on the oncolytic activity of Parvovirus H-1 (H-1PV) in human high-grade glioma cells.

Methods.

Short term cultures of human high-grade gliomas were irradiated at different doses and infected with H-1PV.

Cell viability was assessed by determining relative numbers of surviving cells.

Replication of H-1PV was measured by RT-PCR of viral RNA, fluorescence-activated cell sorter (FACS) analysis and the synthesis of infectious virus particles.

To identify a possible mechanism for radiation induced change in the oncolytic activity of H-1PV we performed cell cycle analyses.

Results.

Previous irradiation rendered glioma cells fully permissive to H-1PV infection.

Irradiation 24 hours prior to H-1PV infection led to increased cell killing most notably in radioresistant glioma cells.

Intracellular levels of NS-1, the main effector of H-1PV induced cytotoxicity, were elevated after irradiation.

S-phase levels were increased one day after irradiation improving S-phase dependent viral replication and cytotoxicity.

Conclusion.

This study demonstrates intact susceptibility of previously irradiated glioma-cells for H-1PV induced oncolysis.

The combination of ionizing radiation followed by H-1PV infection increased viral cytotoxicity, especially in radioresistant gliomas.

These findings support the ongoing development of a clinical trial of H-1PV in patients with recurrent glioblastomas.