Apurinic/apyrimidinic endonuclease activity is associated with response to radiation and chemotherapy inmedulloblastoma and primitive neuroectodermal tumors

Bobola MS, Finn LS, Ellenbogen RG, Geyer JR, Berger MS, Braga JM, Meade EH, Gross ME, Silber JR.

Clin Cancer Res. 2005 Oct 15;11(20):7405-14.

Division of Neurosurgery, Department of Surgery, Children’s Hospital and Regional Medical Center, Seattle, WA 98105, USA.

Purpose

Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair activity that confers resistance to radiation- and alkylator-induced cytotoxic abasic sites in human cells.

We assayedapurinic/apyrimidinic endonuclease activity in medulloblastomas and primitive neuroectodermal tumors(PNET) to establish correlates with tumor and patient characteristics and with response to adjuvantradiation plus multiagent chemotherapy.

Experimental Design

Ap endo activity was assayed in 52 medulloblastomas and 10 PNETs frompatients 0.4 to 21 years old. Ape1/Ref-1, the predominant human Ap endo activity, was measured in 42medulloblastomas by immunostaining.

Cox proportional hazards regression models were used to analyze the association of activity with time to tumor progression (TTP).

Results

Tumor Ap endo activity varied 180-fold and was significantly associated with age and gender.

Tumor Ape1/Ref-1 was detected almost exclusively in nuclei. In a multivariate model, with Ap endoactivity entered as a continuous variable, the hazard ratio for progression after adjuvant treatment in 46medulloblastomas and four PNETs increased by a factor of 1.073 for every 0.01 unit increase in activity (P < or = 0.001) and was independent of age and gender.

Suppressing Ap endo activity in a humanmedulloblastoma cell line significantly increased sensitivity to 1,3-bis(2-chlororethyl)-1-nitrosourea and temozolomide, suggesting that the association of tumor activity with TTP reflected, at least in part, abasicsite repair.

Conclusions

Our data:

  1. Suggest that Ap endo activity promotes resistance to radiation pluschemotherapy in medulloblastomas/PNETs
  2. Provide a potential marker of treatment outcome
  3. Suggest clinical use of Ap endo inhibitors to overcome resistance