Article

Apurinic endonuclease activity in adult gliomas and time to tumor progression after alkylating agent-based chemotherapy and after radiotherapy

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, United States
Clinical Cancer Research (Impact Factor: 8.19). 01/2005; 10(23):7875-83. DOI: 10.1158/1078-0432.CCR-04-1161
Source: PubMed

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

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    • "Numerous reports have described an inverse association between immunopositivity for Ape1 and clinical course in a variety of human tumors (Evans et al., 2000; Abbotts and Madhusudan, 2010). To extend these studies to human gliomas and to evaluate Ap endo activity as a marker of treatment response, we examined the association of Ap endo activity with PFS following sequential treatment with radiation and alkylating agents in 30 anaplastic gliomas and 34 GBMs (Bobola et al., 2004). Cox regression analysis with Ap endo activity entered as a continuous variable revealed an inverse relationship with a HR for progression following alkylator therapy in the anaplastic gliomas increasing by a factor of 1.061 for every 0.01 increase in activity (P = 0.013). "
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