The failure of epigenetic combination therapy for cancer and what it might be telling us about DNA methylation inhibitors

摘要: Epigenetic changes in cancer are well described, and it is believed aberrant DNA hypermethylation histone deacetylation can lead to silencing of tumor suppressor genes tumorigenesis [1]. therapy progressively growing importance as a class therapies for cancer. Currently seven drugs approved by the US FDA treatment variety cancers, target two major epigenetic systems. Those that inhibit methylation those (Table 1). have demonstrated clear benefit patients with some cancers via randomized clinical trials [2,3]. However, conclusive evidence these function an mechanism does not exist. In fact, studies combining been disappointing may suggest agents do act [4–6]. Azacitidine (Vidaza) decitabine (Dacogen) methyltransferase inhibitors (DNMTi). Both cytosine analogs incorporate into irreversibly leading decrease methylation. DNMTi single-agent myelodysplastic syndrome (MDS), hematologic malignancy closely related acute myelogenous leukemia (AML) [7,8]. used at clinically low doses which take advantage inhibition properties opposed cytotoxic drugs. Clinically decreases gene-specific global shown [9,10]; however, reactivation specific gene has be associated response MDS. addition, appear transient rapidly return baseline levels after stopped or between cycles [9]. was compared trial another analog, cytarabine. this study cytarabine given both higher doses. clearly improve survival low-dose high-dose chemotherapy [2]. Interestingly rate complete (eradication disease normalization bone marrow) intensive chemotherapy, but outcome better chronic azacitidine Perhaps contrasting killing strategy versus modification phenotype therapy. The failure combination what might telling us about