Hypomethylating agents for urologic cancers

Abstract

Silencing of tumor suppressor genes by promoter-region methylation as an epigenetic mechanism of gene regulation is increasingly recognized as beneficial in cancer. Initially developed as cytotoxic high-dose therapies, azacitidine and decitabine are now being reinvestigated in lower-dose cancer treatment regimens with a different paradigm – hypomethylation. Recent evidence for benefit in myelodysplastic syndromes and acute myeloid leukemias has renewed interest in hypomethylation as a therapeutic option in epithelial cancers. In this article, we describe the mechanistic aspects of DNA methylation, which alters gene expression, and review the evidence for hypomethylation as a therapeutic option in urologic cancers. Potential correlative studies that may assist in developing tailored therapy with hypomethylating agents are reviewed. Given that the population with urologic cancers is typically elderly with multiple comorbidities, the excellent tolerability of lower-dose hypomethylating agents provides a high therapeutic index and rational development is warranted, bearing in mind that the cytostatic and delayed activity present challenges in the choice of appropriate trial end points.