alexa DNA methyltransferase inhibitors and the development of epigenetic cancer therapies.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Stem Cell Research & Therapy

Author(s): Lyko F, Brown R

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Abstract Epimutations, such as the hypermethylation and epigenetic silencing of tumor suppressor genes, play a role in the etiology of human cancers. In contrast to DNA mutations, which are passively inherited through DNA replication, epimutations must be actively maintained because they are reversible. In fact, the reversibility of epimutations by small-molecule inhibitors provides the foundation for the use of such inhibitors in novel cancer therapy strategies. Among the compounds that inhibit epigenetic processes, the most extensively studied are DNA methyltransferase inhibitors. In this review, we examine the literature on DNA methyltransferase inhibitors and discuss the efficacy of such compounds as antitumor agents, as evaluated in phase I-III clinical trials. We also discuss future areas of research, including the development of nonnucleoside inhibitors, the application of novel bioanalytical tools for DNA methylation analysis (which will be important for the clinical application of these compounds by allowing rational approaches to trial design), the need to optimize treatment schedules for maximal biologic effectiveness, and the need to define molecular endpoints so that changes induced by demethylating drugs in patients can be monitored during treatment. Assays for genome-wide and tumor-specific DNA methylation also need to be further developed to establish the pharmacodynamic parameters of DNA methyltransferase inhibitors in patients and to provide rational approaches to maximizing the therapeutic efficacy of these compounds. This article was published in J Natl Cancer Inst and referenced in Journal of Stem Cell Research & Therapy

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