國家衛生研究院 NHRI:Item 3990099045/2725

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Title:	DNA repair enzyme, O-6-methylguanine DNA methyltransferase, modulates cytotoxicity of camptothecin-derived topoisomerase I inhibitors
Authors:	Kuo, CC;Liu, JF;Chang, JY
Contributors:	National Institute of Cancer Research
Abstract:	Two camptothecin-resistant cell lines, CPT30 and KB100, were established and characterized previously in our laboratory. Because enhanced sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea ( BCNU) and decreased expression of O-6-methylguanineDNA methyltransferase ( MGMT) protein were observed in these lines, we hypothesized that MGMT may be a determinant of cytotoxicity associated with camptothecin-derived DNA topoisomerase I inhibitors ( CPTs). We used the Tet-On system to induce expression of MGMT in Chinese hamster ovary ( CHO) cells and RNA interference to knock down MGMT expression in human nasopharyngeal carcinoma HONE-1 cells in order to identify any correlations between MGMT expression and CPTs cytotoxicity. CHO-derived Tet-On-inducible cells ( S12+) showed MGMT overexpression and statistically significant more resistance to BCNU, camptothecin, 7-ethyl-10-hydrocamptothecin ( SN38), and topotecan than parental CHO cells ( p < 0.05), but there was less resistance to CPTs than to BCNU. Knockdown of MGMT expression with small interfering RNA in HONE-1 cells conferred increased sensitivity to BCNU and CPTs compared with mock control. Furthermore, alteration of MGMT expression coincides with CPT-induced cell death and poly( ADP-ribose) polymerase cleavage. There were no differences in protein levels and catalytic activity of topoisomerase I between MGMT- proficient and MGMT-deficient cells from the Tet-On-inducible and small interfering RNA ( siRNA) systems. Resistance to CPTs coincided with decreased amounts of protein-linked DNA breaks generated by CPTs in MGMT-proficient cells and vice versa in MGMT-deficient cells. Our data indicate that MGMT can modulate cytotoxicity of CPT-derived topoisomerase I inhibitors.
Keywords:	Pharmacology & Pharmacy
Date:	2006-02
Relation:	Journal of Pharmacology and Experimental Therapeutics. 2006 Feb;316(2):946-954.
Link to:	http://dx.doi.org/10.1124/jpet.105.095919
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-3565&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000234759000055
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=31144478509
Appears in Collections:	[Jang-Yang Chang] Conference Papers/Meeting Abstract [Ching-Chuan Kuo] Conference Papers/Meeting Abstract

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