Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy.
OBJECTIVE
Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair enzyme that cleaves DNA at cytotoxic abasic sites caused by alkylating agents and radiation. We have observed that human glioma cells deficient in Ap endo activity are hypersensitive to clinically used alkylators (Silber et al., Clin Cancer Res 2002;8:3008.). Here we examine the association of glioma Ap endo activity with clinical response after alkylating agent-based chemotherapy or after radiotherapy.


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


RESULTS
In a univariate model with Ap endo activity entered as a continuous variable, the hazard ratio (HR) for progression after alkylator therapy in 30 grade III gliomas increased by a factor of 1.061 for every 0.01 increase in activity (P = 0.013). Adjusting for age, gender, extent of resection, and prior treatment strengthened slightly the association (HR = 1.094; P = 0.003). Similarly, the HR for progression after radiotherapy in 44 grade II and III tumors increased by a factor of 1.069 (P = 0.008). Adjusting for the aforementioned variables had little effect on the association. In contrast, we observed no association between activity and TTP in grade IV gliomas after either alkylator therapy in 34 tumors or radiotherapy in 26 tumors.


CONCLUSIONS
Our data suggest that Ap endo activity mediates resistance to alkylating agents and radiation and may be a useful predictor of progression after adjuvant therapy in a subset of gliomas.
Bobola
Michael S
MS
Department of Neurological Surgery, University of Washington, 1959 N.E Pacific Street, Seattle, WA 98195-6470, USA.
Emond
Mary J
MJ
Blank
A
A
Meade
Elizabeth H
EH
Kolstoe
Douglas D
DD
Berger
Mitchel S
MS
Rostomily
Robert C
RC
Silbergeld
Daniel L
DL
Spence
Alexander M
AM
Silber
John R
JR
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D001254:Astrocytoma / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D009837:Oligodendroglioma / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy; D011836:Radiation Tolerance; D011879:Radiotherapy Dosage; D015996:Survival Rate; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase