Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas

Apurinic/apyrimidinie endonuclease (Ap endo) is a key DNA repair activity t hat confers resistance to ionizing radiation and alkylating agents in human cell lines. The major Ap endo in human cells is Ape1, an abundant multi-fu nctional protein also known as Ref-1, Hap-1, and Apex. In this work, we ass ayed Ap endo activity in human adult gliomas to establish correlates with t umor characteristics, and in histologically normal brain adjacent to tumors to characterize changes in activity accompanying neurocarcinogenesis. To o ur knowledge, this is the first available analysis of Ap endo activity in h uman brain tumors. Mean activity in 84 gliomas of different diagnostic type s and grades was 0.072 +/-0.095 fmol abasic sites incised/cell/min; ranging similar to 550-fold from 0.00077 to 0.42. The mean for high-grade gliomas was 3.5-fold greater than for low-grade tumors (P less than or equal to4.0x 10(-5)), a difference observed within all diagnostic types. Activity was co rrelated with the fraction of S-phase cells in diploid gliomas (P less than or equal to0.02), suggesting that proliferation could be a determinant of activity in these tumors. Activity was also correlated with S-phase fractio n in the majority of aneuploid gliomas (P less than or equal to0.03). Moreo ver, within the aneuploid tumors, there was a significant relationship betw een activity and the fraction of aneuploid cells (P less than or equal to4. 0x10(-4)). In, the 58 cases analyzed, mean activity was 7.3-fold higher in gliomas than mi adjacent histologically normal brain (0.070 +/-0.10 versus 0.0096 +/-0.012 fmol/cell/min; P less than or equal to3.0x10(-5)). Increase d tumor activity was observed in 93% of tumor/normal pairs, indicating that elevation of Ap endo activity is characteristic of human gliomagenesis. Th e elevation was large within most pairs, being 13-fold on average and great er than or equal to 10-fold in 43% of cases. A concomitant increase in Ape1 protein was observed by Western blotting in the subset of tumor/normal pai rs, examined. A clinically important consequence of the increase in Ap endo activity that accompanies neurocarcinogenesis may be enhanced resistance t o the radiotherapy and alkylating agent-based chemotherapy that are mainsta ys of adjuvant therapy for malignant gliomas.