The list of genes

reported to be methylated in haematological neoplasms is extensive, and although several have been linked to clinical parameters and have been associated with survival or buy GDC-0068 response to treatment, none of these markers has been used so far in the clinic to guide diagnosis or treatment, as opposed to gene mutations such as NPM1 and FLT3 that are now widely used to risk classify AML patients. One of the major goals of investigators in oncology is that of individualized Inhibitors,research,lifescience,medical cancer therapy. Investigators continue to identify genes whose transcriptional silencing affects sensitivity to chemotherapeutic agents. The challenge now is to translate these findings into clinically usable tests to inform optimal deployment of anticancer drugs. It remains unlikely that a single gene methylation test will be sufficiently informative to guide individual patient management and it is more likely that panels of genes will be

required. 5.2. Cancer Therapeutics Both epigenetic proteins and protein markers are good targets Inhibitors,research,lifescience,medical for the development Inhibitors,research,lifescience,medical of new anticancer treatments. The proof-of-concept for epigenetic therapies is the FDA and EMEA approval of demethylating agents and histone acetylase (HDAC) inhibitors for the treatment of MDS, AML and certain types of lymphomas, respectively. However, we should not forget that these agents are nonselective and their side effects are not clearly known. 5.2.1. DNA Methyltransferase Inhibitors (DNMTis) or Demethylating Agents The two most well studied and in clinical use DNA methyltransferase inhibitors (DNMTi) are the azanucleosides azacytidine (5-azacytidine) and decitabine (5-aza′-2-deoxycytidine). Inhibitors,research,lifescience,medical Both are approved for use in the myelodysplastic syndromes and low-blast count AML and Inhibitors,research,lifescience,medical have improved the survival of patients with these diseases [57]. Unfortunately, clinical trials with DNMTi in

solid tumours did not have the same results. A phase 1 study of decitabine with interleukin-2 in melanoma and renal cell carcinoma showed that decitabine caused grade 4 neutropenia in most patients [58]. Myelosuppression was also the predominant toxicity observed in a study combining decitabine with carboplatin [59]. However, in a phase II trial low-dose decitabine was found to restore sensitivity to carboplatin in patients with heavily pretreated ovarian cancer from resulting in a high response rate (RR) and prolonged PFS [60]. In both studies, there was evidence that decitabine induced dose-dependent demethylation in marker genes such as MLH1, RASSF1A, HOXA10, and HOXA11 [60]. It is possible that such an approach could efficiently be coupled with the use of epigenetic biomarkers predictive of chemosensitivity [56]. A major likely reason for the disappointing activity of demethylating agents in solid tumours is limited incorporation into cells, which are proliferating relatively slowly.