PMID- 20442312 OWN - NLM STAT- MEDLINE DCOM- 20100820 LR - 20220309 IS - 1538-8514 (Electronic) IS - 1535-7163 (Print) IS - 1535-7163 (Linking) VI - 9 IP - 5 DP - 2010 May TI - S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. PG - 1443-50 LID - 10.1158/1535-7163.MCT-09-1048 [doi] AB - Methylation of CpG islands in promoter regions is often associated with gene silencing and aberrant DNA methylation occurs in most cancers, leading to the silencing of some tumor suppressor genes. Reversal of this abnormal hypermethylation by DNA methylation inhibitors is effective in reactivating methylation-silenced tumor suppressor genes both in vitro and in vivo. Several DNA methylation inhibitors have been well studied; the most potent among them is 5-aza-2'-deoxycytidine (5-Aza-CdR), which can induce myelosuppression in patients. S110 is a dinucleotide consisting of 5-Aza-CdR followed by a deoxyguanosine, which we previously showed to be effective in vitro as a DNA methylation inhibitor while being less prone to deamination by cytidine deaminase, making it a promising alternative to 5-Aza-CdR. Here, we show that S110 is better tolerated than 5-Aza-CdR in mice and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding tumor growth in human xenograft. We also show that S110 is effective by both i.p. and s.c. deliveries. S110 therefore is a promising new agent that acts similarly to 5-Aza-CdR and has better stability and less toxicity. FAU - Chuang, Jody C AU - Chuang JC AD - Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. FAU - Warner, Steven L AU - Warner SL FAU - Vollmer, David AU - Vollmer D FAU - Vankayalapati, Hariprasad AU - Vankayalapati H FAU - Redkar, Sanjeev AU - Redkar S FAU - Bearss, David J AU - Bearss DJ FAU - Qiu, Xiangning AU - Qiu X FAU - Yoo, Christine B AU - Yoo CB FAU - Jones, Peter A AU - Jones PA LA - eng GR - 5 T32 GM067587/GM/NIGMS NIH HHS/United States GR - R01 CA082422-01/CA/NCI NIH HHS/United States GR - R37 CA082422-11/CA/NCI NIH HHS/United States GR - R01 CA082422/CA/NCI NIH HHS/United States GR - 5R37CA82422/CA/NCI NIH HHS/United States GR - R37 CA082422/CA/NCI NIH HHS/United States GR - T32 GM067587-01/GM/NIGMS NIH HHS/United States GR - T32 GM067587/GM/NIGMS NIH HHS/United States GR - R01 CA083867/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20100504 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Oligonucleotides) RN - 0 (S110 compound) RN - 776B62CQ27 (Decitabine) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases) RN - M801H13NRU (Azacitidine) SB - IM MH - Animals MH - Antimetabolites, Antineoplastic/*pharmacology/therapeutic use MH - Azacitidine/*analogs & derivatives/chemistry/pharmacology/therapeutic use MH - Cell Line, Tumor MH - Cell Proliferation/*drug effects MH - DNA (Cytosine-5-)-Methyltransferases/*antagonists & inhibitors MH - DNA Methylation/drug effects MH - Decitabine MH - Down-Regulation/drug effects MH - Female MH - Humans MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Models, Biological MH - Neoplasms/drug therapy/*pathology MH - Oligonucleotides/*pharmacology/therapeutic use MH - Treatment Outcome MH - Tumor Burden/*drug effects MH - Xenograft Model Antitumor Assays PMC - PMC2868087 MID - NIHMS188847 EDAT- 2010/05/06 06:00 MHDA- 2010/08/21 06:00 PMCR- 2011/05/04 CRDT- 2010/05/06 06:00 PHST- 2010/05/06 06:00 [entrez] PHST- 2010/05/06 06:00 [pubmed] PHST- 2010/08/21 06:00 [medline] PHST- 2011/05/04 00:00 [pmc-release] AID - 1535-7163.MCT-09-1048 [pii] AID - 10.1158/1535-7163.MCT-09-1048 [doi] PST - ppublish SO - Mol Cancer Ther. 2010 May;9(5):1443-50. doi: 10.1158/1535-7163.MCT-09-1048. Epub 2010 May 4.