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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/6133
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| Title: | DNA repair enzyme, O6-methylguanine DNa methyltransferase, modulates therapeutic efficacy of platinum drugs with radiation and its clinical significance |
| Authors: | Chen, SH;Yang, YN;Li, CF;Huang, HY;Liu, JF;Kuo, CC;Chang, JY |
| Contributors: | National Institute of Cancer Research |
| Abstract: | Background: In this study, we were aiming to evaluate the role of DNA repair enzyme, O6-methylguanine–DNA methyltransferase (MGMT) in regulating the therapeutic efficacy of platinum drugs and radiation, and also investigate its clinical significance. Materials and Methods: Tetracycline-regulated Tet-On system and RNA interference method were used to investigate the correlations between MGMT expression and platinums/radiation-induced DNA damage and cytotoxicity in cultured cells. Furthermore, 83 NPC patients received cisplatin (CDDP)-based concurrent chemoradiotherapy (CCRT) were analyzed the relationship of MGMT expression and survival. Results: CHO-derived Tet-On-inducible cells (S12+) showed MGMT overexpression and statistically significant more resistance to CDDP, carboplatin and oxaliplatin than parental CHO cells. Knockdown of MGMT expression with small interfering RNA in HONE-1 cells conferred increased sensitivity to those platinum drugs as compared with scrambled control. Further study showed that the amount of CDDP-DNA adduct and double strand DNA breaks after CDDP exposure were significantly lower in MGMTproficient cells than that of MGMT-deficient cells in both Tet-On and RNAi system. Host reactivation assay revealed that protection of CDDP-induced DNA damage and cell death by MGMT is through enhanced global DNA repair capacity. Otherwise, Resistance to X-ray irradiation was observed in MGMT-proficient cells, and vice versa in MGMT-deficient cells. The result from clinical specimens revealed that the NPC patients, who received CDDP-based CCRT, with lower level of MGMT expression had a better disease-free survival (DSS) (P = 0.015) and local recurrent-free survival (LRFS) (p < 0.05) than patients with high expression of MGMT. Multivariate analyses indicated that high expression of MGMT is an independent predictor for poor survival, with a risk ratio of 2.14 for DSS (95% CI=1.14–4.02), and 3.62 for LRFS (95% CI=1.33–9.88). Conclusion: Our results suggested that MGMT plays an important role in determining the therapeutic efficacy of platinum drugs and radiation, and may have a relevance to clinical use of CCRT. |
| Date: | 2011-09 |
| Relation: | European Journal of Cancer. 2011 Sep;47:S132. |
| Link to: | http://dx.doi.org/10.1016/S0959-8049(11)70772-9 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0959-8049&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000295752800466 |
| Appears in Collections: | [郭靜娟] 會議論文/會議摘要
[張俊彥] 會議論文/會議摘要
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| ISI000295752800466.pdf | | 40Kb | Adobe PDF | 689 | View/Open |
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