Carcinogenesis Advance Access published online on December 19, 2003
Carcinogenesis, doi:10.1093/carcin/bgh045
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 McGill University, Department of Pharmacology and Therapeutics, 3655 Sir William Osler Promenade, Montreal, Quebec H3G1Y6, Canada
* Corresponding author. E-mail: mszyf{at}pharma.mcgill.ca.
Received 16 July 2003
; revised 18 November 2003
; accepted 30 November 2003
Methylated DNA binding protein 2 (MBD2) has been proposed to function both as a silencer of methylated genes and as a DNA demethylase. Our previous data indicated that knock down of MBD2 inhibited tumorigenesis of human cancer lines and MBD2 deficient mice were recently shown to be resistant to intestinal tumorigenesis. MBD2 is an attractive anticancer target since MBD2 deficient mice were previously shown to be viable and fertile and knock down of MBD2 was reported to have no effect on cellular growth parameters of nontransformed cells. In this paper we test the hypothesis that pharmacological inhibition of MBD2 inhibits cancer growth in vivo using human tumour lines implanted in mice as a model. We develop sequence specific antisense inhibitors of MBD2 and we show that these agents inhibit anchorage-independent growth of human lung (A549) and colorectal (HCT116) cancer cell lines in vitro and tumorigenic growth of human cancer cell xenografts in vivo. MBD2 antisense oligonucleotide does not inhibit the growth of normal and transformed cell lines and does not alter cell cycle parameters in vitro and does not exhibit overt toxicity in vivo in comparison with a scrambled control oligonucleotide as determined by measuring body mass, blood cell parameters and liver and kidney enzymes. Our data provides a proof of principle that MBD2 is a new anticancer target and that pharmacological inhibition of MBD2 by agents such as the antisense inhibitors described in this paper are potential new anticancer therapeutics, which in contrast to the vast majority of current approaches do not target the normal progression of the cell cycle.
Methylated DNA binding proteins, tumorigenesis, DNA demethylase, antisense oligonucleotides, anticancer agents
Methylated DNA binding protein 2 antisense inhibitors suppress tumorigenesis of human cancer lines in vitro and in vivo
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