Improved killing of human high-grade glioma cells by combining ionizing radiation with oncolytic parvovirus H-1 infection.
OBJECTIVE
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.


CONCLUSIONS
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.
Geletneky
Karsten
K
Department of Neurosurgery, University of Heidelberg, Heidelberg 69120, Germany. kgeletneky@med.uni-heidelberg.de
Hartkopf
Andreas D
AD
Krempien
Robert
R
Rommelaere
Jean
J
Schlehofer
Joerg R
JR
D002453:Cell Cycle / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects*; D003131:Combined Modality Therapy; D005910:Glioma / Q000503:physiopathology* / Q000821:virology*; D052661:H-1 parvovirus / Q000502:physiology* / Q000528:radiation effects*; D006801:Humans; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology* / Q000528:radiation effects