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Mol Cancer Ther. 2004;3:123-127
© 2004 American Association for Cancer Research

Dual repair modulation reverses Temozolomide resistance in vitro

Vincent A. Barvaux1, Malcolm Ranson1, Robert Brown2, R. Stanley McElhinney3, T. Brian H. McMurry3 and Geoffrey P. Margison1

1 Paterson Institute for Cancer Research and Christie Hospital, Manchester, United Kingdom; 2 Cancer Research United Kingdom Beatson Laboratories, Glasgow University, Glasgow, United Kingdom ; and 3 University Chemical Laboratory, Trinity College, Dublin, Ireland

Requests for Reprints:Geoffrey P. Margison, Paterson Institute for Cancer Research, Wilmslow Road, Manchester, M204BX, United Kingdom.

Temozolomide is an alkylating agent that mediates its cytotoxic effects via O6-methylguanine (O6-meG) adducts in DNA and their recognition and processing by the postreplication mismatch repair system (MMR). O6-meG adducts can be repaired by the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (MGMT), which therefore constitutes a major resistance mechanism to the drug. Resistance to Temozolomide can also be mediated by loss of MMR, which is frequently mediated by methylation of the hMLH1 gene promoter. Methylation of hMLH1 can be reversed by treatment of cells with 5-aza-2'-deoxycytidine, while the MGMT pseudosubstrate O6-(4-bromothenyl)guanine (PaTrin-2) can deplete MGMT activity. Using a drug-resistant cell line which expresses MGMT and has methylated hMLH1, we show that while either of these treatments can individually sensitize cells to Temozolomide, the combined treatment leads to substantially greater sensitization. The increased sensitization is not observed in matched MMR proficient cells.

Grant support:European Union Marie Curie Individual Fellowship (proposal no. 2000-02021); the Bourse post-doctorale de recherche scientifique (Mai 2000) of the Universite Catholique de Louvain, Belgium; and Cancer Research United Kingdom.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/30/03; revised 10/30/03; accepted 11/ 3/03.






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Copyright © 2004 by the American Association for Cancer Research.