**Antioxidant Adaptive Response in Glioma**

244 Novel Therapeutic Concepts in Targeting Glioma

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**12** 

*Japan*

**Antioxidant Adaptive Response** 

**of Malignant Glioma Related to** 

Tomohiro Sawa and Takaaki Akaike

**Resistance to Antitumor Treatment** 

*Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University* 

Glioblastomas are the most frequent and most malignant nervous system tumors [Stewart & Kleihues, 2003]. Despite technological advances in surgical treatment and new regimens of radiotherapy combined with chemotherapy, the median survival of patients with these tumors is approximately 1 year, and only 3% of patients survive more than 3 years [Stupp et al., 2005]. Glioblastomas have been traditionally defined as two clinically and cytogenetically distinct diseases: the primary or de novo glioblastomas and the secondary glioblastomas. The latter commonly appear in younger people (median age at onset ~45 years) as low-grade gliomas and possess aberrations in genes encoding platelet-derived growth factor receptor (*PDGFR*) and *TP53* [Stewart & Kleihues, 2003]. Primary glioblastomas occur more frequently (>80% of cases) and develop rapidly in older people (median age at onset ~60 years); survival of patients with such tumors is short, less than 3 months [Stewart & Kleihues, 2003]. The genetic profile of primary glioblastomas includes amplification and overexpression of the gene encoding epidermal growth factor receptor (*EGFR*), mutations of the phosphatase and tensin homolog (*PTEN*) gene, *p16INK4A* deletions, and loss of chromosome 10 [Stewart & Kleihues, 2003]. Several inhibitors that target *EGFR* or its downstream signaling cascade including Akt and mTOR have been evaluated for potential application in glioblastoma treatment [Krakstad & Chekenya, 2010]. Recent clinical trials of *EGFR* inhibitors, however, showed no therapeutic

Chemotherapy plays an important role in combined treatment of gliomas, whereas it appears to fail in a significant clinical outcome. This may be largely due to drug resistance of malignant gliomas developed [Lu & Shervington, 2008; Sarkaria, et al, 2008; Frosina, 2009; Bleau et al., 2009]. Multiple mechanisms may be involved in the development of drug resistance in gliomas, including DNA repair enzyme activities, particularly O6 methylguanine methyltransferase for alkylating agents, overexpression of antiapoptotic proteins such as Bcl-2 or Bcl-XL and ABC transporters that efflux anticancer drugs. Clarification of mechanisms for glioma drug resistance may provide us an important insight

A number of studies have suggested that heme oxygenase-1 (HO-1) expression occurs in various types of tumors, both animal models and human cancers including glioblastomas

for the development of promising strategies for the treatment of gliomas.

**1. Introduction** 

benefit [Prados et al., 2006; Rich et al., 2004].
