title: Apurinic/apyrimidinic endonuclease is inversely associated with response to radiotherapy in pediatric ependymoma.
abstract: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers radiation resistance in human cells. Here we examined the association between Ap endo activity and response to radiotherapy in pediatric ependymomas, tumors for which treatment options are limited and survival rates are only about 50%. We assayed Ap endo activity in 36 ependymomas and expression of Ape1/Ref-1, the predominant Ap endo activity in humans, in 44 tumors by immunostaining. Cox proportional hazards regression models were used to analyze the association of activity or expression with progression-free survival or with overall survival. Activity varied 13-fold and was not associated with tumor or patient characteristics. In univariate models with Ap endo activity entered as a continuous variable, the hazard ratio for progression increased by a factor of 2.18 for every 0.01 unit increase in activity (p ≤ 0.003) in 24 grade II ependymomas. Risk for death increased by a factor of 1.89 (p ≤ 0.02) in the same population. The fraction of Ape1/Ref-1 immunopositive cells varied widely within individual tumors and was not associated with either progression-free or with overall survival. Suppressing Ap endo activity in pediatric ependymoma cells significantly increased radiation sensitivity, suggesting that the association of activity with radiation response reflected, at least in part, repair of radiation-induced DNA lesions. Our data indicate that Ap endo activity is predictive of outcome following radiotherapy, and suggest that Ape1/Ref-1 promotes radiation resistance in pediatric ependymomas. Our findings support the use of inhibitors of Ap endo activity to overcome resistance.
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA 98195-6470, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bobola
authors.forename: Pawel P
authors.initials: PP
authors.lastname: Jankowski
authors.forename: Mary E
authors.initials: ME
authors.lastname: Gross
authors.forename: Jeffery
authors.initials: J
authors.lastname: Schwartz
authors.forename: Laura S
authors.initials: LS
authors.lastname: Finn
authors.forename: A
authors.initials: A
authors.lastname: Blank
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ellenbogen
authors.forename: John R
authors.initials: JR
authors.lastname: Silber
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000401:mortality / Q000532:radiotherapy*; D002648:Child; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D018572:Disease-Free Survival; D004806:Ependymoma / Q000201:enzymology* / Q000276:immunology / Q000401:mortality / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011836:Radiation Tolerance
chemical_list: D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase