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485 APURINIC/APYRIMIDINIC ENDONUCLEASE ACTIVITY CONTRIBUTES TO RESISTANCE IN EPENDYMOMAS.
  1. P. P. Jankowski1,
  2. A. M. Avellino1,2,3,
  3. M. S. Bobola1,2,3
  1. 1University of Washington School of Medicine
  2. 2Department of Neurosurgery
  3. 3Children's Hospital and Regional Medical Center, Seattle, WA

Abstract

Background Ependymomas are brain tumors with a 10-year recurrence rate of 90-95% with local distribution; 5-year progression-free survival rates in children currently are approximately at around 14%. Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair enzyme that confers resistance to radiation-induced cytoxic abasic sites in human cells. We assayed Ap endo activity in ependymomas to establish correlates with tumor and patient characteristics and with response to adjuvant radiation therapy.

Study Design and Methods In cell lines Ap endo activity was suppressed by transfection with antisense siRNA and exposed to radiation. Suppression of Ap endo activity was accompanied by increased sensitivity to radiation. In vivo, Ap endo activity was assayed from 21 ependymomas from patients at Children's Hospital and Regional Medical Center of which 11 tumors progressed following radiation. Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP).

Results In a multivariate model, with Ap endo activity entered as a continuous variable, the hazard ratio for progression after radiation treatment in 21 individuals increased by a factor of 1.34 for every 0.01 unit increase in activity (p < .02) and was independent of age and gender. Suppressing Ap endo activity in a human ependymoma cell line significantly increased sensitivity to adjuvant radiation treatment suggesting that the association of tumor activity with TTP partially indicated abasic site repair.

Conclusion Our results suggest that apurinic endonuclease activity may provide resistance to radiation therapy and serve as a predictive marker to treatment response and suggest that the use of Ap endo inhibitors has the ability to be clinically efficacious in overcoming resistance.

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