Cancer Spectrum: Aghi et al., pp. = 38-50.

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Go To: Home >=20 Archive=20 > Vol.=20 98, No. 1 > Aghi et al., pp. 38-50.=20

Journal of the National Cancer Institute, Vol. 98, No. = 1, 38-50,=20 January 4, 2006
DOI: 10.1093/jnci/djj003

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=A9= The=20 Author 2006. Published by Oxford University Press.

ARTICLE

Effect of Chemotherapy-Induced DNA Repair on Oncolytic Herpes = Simplex=20 Viral Replication

Manish Aghi, Samuel Rabkin,=20 Robert L. Martuza=20

Affiliation of authors: Department of=20 Neurosurgery, Massachusetts General Hospital, Harvard Medical = School,=20 Boston, MA

Correspondence to: Manish Aghi, MD, PhD, = Brain=20 Tumor Research Center, Massachusetts General Hospital=96Simches = Research=20 Bldg., 185 Cambridge St., CPZN-3800, Boston, MA 02114 (e-mail: = maghi{at}partners.org ).

Background: Gliomas treated with the = alkylating=20 agent temozolomidehave incomplete responses in part = because of=20 tumoral repairof chemotherapy-induced DNA damage. Data = from=20 phase I trialssuggest that G207, an oncolytic herpes = simplex=20 virus (HSV) withmutated ribonucleotide reductase (RR) = and 34.5 genes, is safebut needs greater viral = oncolysis=20 to be effective. We hypothesizedthat temozolomide and = G207=20 treatment limitations could be jointlyaddressed using=20 temozolomide-induced tumor-protective DNA repair⁼pathways to=20 enhance viral replication. Methods: Human glioblastoma⁼cells (U87, T98, and U373) and U87 cells transfected with = the⁼²⁰gene for the DNA repair enzyme O⁶-methylguanine = DNA=20 methyltransferase(MGMT) were treated with G207 and/or=20 temozolomide. Drug interactions,expression of the = growth=20 arrest DNA damage 34 (GADD34) and RRtranscripts before = and=20 after their knockdown with short interferingRNAs, DNA = strand=20 breaks, and apoptosis were measured using Chou=96Talalay⁼²⁰analysis, real-time reverse transcription=96polymerase = chain⁼²⁰reaction, the comet assay, and flow cytometry, = respectively.⁼²⁰Survival of mice (groups of ten) with intracranial U87=20 xenografttumors treated with temozolomide and/or G207 = was=20 analyzed usingKaplan=96Meier analysis. Results: = Temozolomide exhibitedstrong synergy with G207 in both = MGMT-negative and the MGMTinhibitor=20 O⁶-benzylguanine=96treated MGMT-expressing gliomas⁼(Chou=96Talalay combination indices =3D 0.005 to 0.39) = and⁼²⁰induced GADD34 expression primarily in nonapoptotic=20 MGMT-negativeU87 glioma cells (fold difference =3D 16, = 95%=20 confidence interval[CI] =3D 12.6 to 20.4, compared = with=20 untreated cells). MGMT-expressingT98 and U87/MGMT = cells=20 treated with temozolomide plus O⁶-benzylguanine⁼had=20 higher RR expression than untreated cells (fold difference⁼²⁰=3D14.9, 95% CI =3D 10.1 to 22.0 [T98]; 9.9, 95% CI =3D 7.0 = to 13.8⁼²⁰[U87/MGMT]). GADD34 and RR knockdown increased=20 temozolomide-inducedDNA damage and inhibited the = synergy of=20 G207 and temozolomidein U87 and=20 O⁶-benzylguanine=96treated U87/MGMT cells. Mice⁼²⁰bearing intracranial U87 tumors survived longer after=20 combinationtherapy (100% survival at 90 days) than = after=20 single-agent therapy(median survival =3D 46 and 48 = days with=20 G207 and temozolomidetreatment, respectively).=20 Conclusions: Temozolomide-inducedDNA repair = pathways=20 vary with MGMT expression and enhance HSV-mediated⁼oncolysis in=20 glioma cells. These findings unveil the potentialof = HSV to=20 target cells surviving temozolomide treatment.

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