TY - JOUR
T1 - Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase
AU - Stanziale, Stephen F.
AU - Petrowsky, Henrik
AU - Joe, John K.
AU - Roberts, Gretchen D.
AU - Zager, Jonathan S.
AU - Gusani, Niraj J.
AU - Ben-Porat, Leah
AU - Gonen, Mithat
AU - Fong, Yuman
N1 - Funding Information:
Supported in part by grants RO1 CA75416 (Y.F.), RO1 CA72632 (Y.F.), and RO1CA61524 (Y.F.) from the National Institutes of Health and MBC-99366 (Y.F.) from the American Cancer Society.
PY - 2002/8
Y1 - 2002/8
N2 - 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 γ134.5 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.
AB - 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 γ134.5 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.
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U2 - 10.1067/msy.2002.125715
DO - 10.1067/msy.2002.125715
M3 - Article
C2 - 12219034
AN - SCOPUS:0036676077
SN - 0039-6060
VL - 132
SP - 353
EP - 359
JO - Surgery
JF - Surgery
IS - 2
ER -