XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta

Posters
28.
COMParaTIve STUDY of HYPOMETHYLaTING
aCTIvITIES of 5-azaCYTIDINE CONGENErs
Marika Matoušová, Ivan Votruba, Miroslav Otmar and Helena Mertlíková-Kaiserová
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech
Republic, Gilead Sciences & IOCB Research Center, 166 10 Prague, Czech Republic
Cancer cells often display aberrant hypermethylation which leads to transcriptional
inactivity of various gene groups (such as tumor suppressor genes) and is therefore
responsible for genomic instability. The use of hypomethylating agents as anticancer
drugs is intended for reactivate methylation-silenced genes by decreasing the overall
methylation level. Since epigenetic therapy is expected to be more specific, less toxic
and more effective than standard chemotherapy, the search for new hypomethylating
agents is a top-priority task.
The goal of this study was to compare hypomethylating activity of a series of 5-azacytidine
congeners vs. decitabine and zebularine, the well-established DNA methyltransferase
inhibitors. Quantitative methylation-specific PCR was employed to detect the efficiency
of individual agents on thrombospondin-1 and cyclin-dependent kinase inhibitor 2B
hypermethylated gene loci. Overall changes in DNA methylation level were quantified
by direct detection of 5-methylcytosines by HPLC using digested genomic DNA.
2´-Deoxy-5,6-dihydro-5-azacytidine was identified as a promising drug candidate for
epigenetic therapy. It has similar hypomethylating activity as decitabine, the most effective
hypomethylating drug tested, and is less cytotoxic.
Acknowledgments: Research project of the Institute #OZ40550506; Project #1M0508 by
the Ministry of Education, Youth and Sports of the Czech Republic.
XXII. Biochemistry Congress, Martin
145