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: 8.72). 01/2005; 10(23):7875-83. DOI: 10.1158/1078-0432.CCR-04-1161
Source: PubMed


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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    ABSTRACT: Alkylating agents have long played a central role in the adjuvant therapy of glioblastoma (GBM). More recently, inclusion of temozolomide (TMZ), an orally administered methylating agent with low systemic toxicity, during and after radiotherapy has markedly improved survival. Extensive in vitro and in vivo evidence has shown that TMZ-induced O(6)-methylguanine (O(6)-meG) mediates GBM cell killing. Moreover, low or absent expression of O(6)-methylguanine-DNA methyltransferase (MGMT), the sole human repair protein that removes O(6)-meG from DNA, is frequently associated with longer survival in GBMs treated with TMZ, promoting interest in developing inhibitors of MGMT to counter resistance. However, the clinical efficacy of TMZ is unlikely to be due solely to O(6)-meG, as the agent produces approximately a dozen additional DNA adducts, including cytotoxic N3-methyladenine (3-meA) and abasic sites. Repair of 3-meA and abasic sites, both of which are produced in greater abundance than O(6)-meG, is mediated by the base excision repair (BER) pathway, and occurs independently of removal of O(6)-meG. These observations indicate that BER activities are also potential targets for strategies to potentiate TMZ cytotoxicity. Here we review the evidence that 3-meA and abasic sites mediate killing of GBM cells. We also present in vitro and in vivo evidence that alkyladenine-DNA glycosylase, the sole repair activity that excises 3-meA from DNA, and Ape1, the major human abasic site endonuclease, mediate TMZ resistance in GBMs and represent potential anti-resistance targets.
    Full-text · Article · Nov 2012 · Frontiers in Oncology
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    • "Ubiquitin-induced APE1 degradation may sensitize cells to apoptosis. While APE1 gene downregulation is followed by apoptotic cell death (4,5,24,25), a higher expression of APE1 is linked to chemo/radiation-resistant cancer cells (26–29). As researchers attempt to improve the outcomes of non-invasive treatments for tumors (30,31), the mechanism involved in APE1 ubiquitination is an important subject to understand. "
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    ABSTRACT: Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5. We here report that ubiquitination of T233E APE1, a mimicry of phospho-T233 APE1, was markedly increased in multiple cell lines. Expression of CDK5 enhanced monoubiquitination of endogenous APE1. Polyubiquitinated APE1 was decreased when K48R ubiquitin was expressed, suggesting that polyubiquitination was mediated mainly through Lys48 of ubiquitin. The ubiquitination activity of MDM2, consistent in its role for APE1 ubiquitination, was increased for T233E APE1 compared to the wild-type APE1. In mouse embryonic fibroblasts lacking the MDM2 gene, ubiquitination of T233E APE1 was still observed probably because of the decreased degradation activity for monoubiquitinated APE1 and because of backup E3 ligases in the cells. Monoubiquitinated APE1 was present in the nucleus, and analyzing global gene expression profiles with or without induction of a ubiquitin-APE1 fusion gene suggested that monoubiquitination enhanced the gene suppression activity of APE1. These data reveal a delicate balance of ubiquitination and phosphorylation activities that alter the gene regulatory function of APE1.
    Full-text · Article · Jul 2011 · Nucleic Acids Research
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    • "implying that this chromosome region contains genes important for BCNU resistance (Hank et al., 2006). Resistance of gliomas to alkylators and recurrence of disease after therapy with alkylators are also proportional to the activity in these tumors of apurinic/apyrimidinic endonuclease, a DNA repair enzyme that cleaves DNA at the abasic sites formed by alkylating chemotherapy and radiation (Bobola et al., 2004). "
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    ABSTRACT: Tumors of the adult central nervous system are among the most common and most chemoresistant neoplasms. Malignant tumors of the brain and spinal cord collectively account for approximately 1.3% of all cancers and 2.2% of all cancer-related deaths. Novel pharmacological approaches to nervous system tumors are urgently needed. This review presents the current approaches and challenges to successful pharmacotherapy of adults with malignant tumors of the central nervous system and discusses novel approaches aimed at overcoming these challenges.
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