A second explanation for these results

is that agents suc

A second explanation for these results

is that agents such as azacytidine, which cause global hypomethylation, likely reactivate expression of multiple silenced genes including oncogenes and tumour suppressors in different cell types and in different cancers. Demethylation could therefore cause both therapeutic and deleterious effects. For example, Inhibitors,research,lifescience,medical the oncogene NT5E is overexpressed in aggressive metastatic melanomas, yet transcriptionally silenced by methylation in breast cancer with more favorable prognosis [61]. A third and key possible explanation why DNMTi have advanced less rapidly in the clinic in solid tumours than in haematological malignancies is that of toxicity. Both decitabine and azacytidine are active in haematological malignancy at lower (less toxic) doses than are required for demethylation in epithelial malignancies. It is clearly of interest, therefore, that transient exposure of cells to low (relatively non-toxic) Inhibitors,research,lifescience,medical doses of these agents could induce a “memory” response with sustained reduction in CpG island methylation and reactivation of expression of previously silenced genes [62]. These observations imply that low-dose decitabine and azacytidine may have

wider uses in Inhibitors,research,lifescience,medical management of neoplastic disease than previously believed. In a recently reported phase II trial Matei et al. [60] showed that pretreatment with low-dose azacytidine restored sensitivity to Inhibitors,research,lifescience,medical carboplatin in patients with drug resistant epithelial ovarian cancer and resulted in a high response rate and significantly improved clinical outcomes. This study clearly attests to the utility of low-dose azacytidine in solid tumours and sets the scene for further Inhibitors,research,lifescience,medical studies. Newer azanucleosides are zebularine, S-110, and SGI-1027 that

have shown antiproliferative activity in cell lines [63, 64], but have not entered the clinical trial setting yet. 5.2.2. Histone Deacetylase Inhibitors (HDACi) The HDACs catalyse removal of acetyl groups from lysine residues in the histones and functionally are transcriptional repressors. HDACs are divided into five classes: class I comprises HDAC1, HDAC2, HDAC3, and HDAC8; class IIa comprises HDAC4, HDAC5, HDAC7, and HDAC9; class of IIb contains HDAC6 and HDAC10; class III comprises the sirtuins SIRT1-SIRT7 while class IV contains only HDAC11 [65]. The discovery of HDACi actually preceded the discovery of HDACs. Sodium SB-715992 research buy butyrate was the first HDACi described to induce acetylation [66], and later on trichostatin (TSA), a fungal antibiotic, currently used in in vitro experiments, and valproic acid, a widely used antiepileptic, were identified. Valproic acid, in particular, has been used in combination with DNMTi and/or chemotherapy in patients with haematological malignancies [67, 68].

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