Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase.
BACKGROUND
Replication-competent herpes simplex virus-1 (HSV-1) mutants have an oncolytic effect on human and animal cancers. The aim of this study was to determine whether G207, an HSV-1 mutant, can be combined with ionizing radiation (IR) to increase antitumor activity while decreasing treatment-associated toxicity.


METHODS
This study was performed by using G207, a replication-competent HSV-1 mutant deficient in viral ribonucleotide reductase (RR) and the gamma(1)34.5 neurovirulence protein. The antitumor activity of G207 or IR was tested against HCT-8 human colorectal cancer cells in vitro and in an in vivo mouse subcutaneous tumor model.


RESULTS
We demonstrated that G207 has significant oncolytic effect on HCT-8 cells in vitro in a cytotoxicity assay and in vivo in a mouse flank tumor model and that these effects are improved with low-dose IR. We further illustrated that the increased tumoricidal effect is dependent on the up-regulation of cellular RR by IR measured by a functional bioassay for RR activity. Chemical inhibition of RR by hydroxyurea abrogates the enhanced effect. In contrast to G207, R3616, the parent virus of G207 that expresses functional RR, does not exhibit enhanced oncolysis when combined with IR.


CONCLUSIONS
These data encourage clinical investigation of combination radiation therapy and HSV oncolytic therapy.
Stanziale
Stephen F
SF
Hepatobiliary Division, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Petrowsky
Henrik
H
Joe
John K
JK
Roberts
Gretchen D
GD
Zager
Jonathan S
JS
Gusani
Niraj J
NJ
Ben-Porat
Leah
L
Gonen
Mithat
M
Fong
Yuman
Y
D000818:Animals; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D015179:Colorectal Neoplasms / Q000628:therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D015967:Gene Expression Regulation, Viral / Q000528:radiation effects; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics / Q000528:radiation effects*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D066298:In Vitro Techniques; D007763:Lac Operon; D051379:Mice; D054645:Protein Phosphatase 1; D011506:Proteins / Q000235:genetics; D011839:Radiation, Ionizing; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000821:virology; D015854:Up-Regulation / Q000528:radiation effects; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000528:radiation effects
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011506:Proteins; D014764:Viral Proteins; D012264:Ribonucleotide Reductases; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1; D006918:Hydroxyurea