Hypomethylating

Hypomethylating refers to a reduction in DNA methylation, a chemical modification in which methyl groups are added to cytosine bases in DNA. DNA methylation is an epigenetic mechanism that helps regulate gene expression, genomic imprinting, and chromatin structure. Hypomethylation can lead to the reactivation of genes that have been silenced by excessive methylation. In health, methylation patterns are dynamic and coordinated; in disease, especially certain cancers, abnormal methylation can contribute to disrupted gene regulation.

Hypomethylating agents are a class of drugs that deliberately induce DNA demethylation by inhibiting DNA methyltransferases, the enzymes that add methyl groups to DNA. The most widely used hypomethylating agents include azacitidine, decitabine, and guadecitabine. These drugs are incorporated into cellular nucleic acids and trap DNMT enzymes, leading to passive demethylation during DNA replication and, in some contexts, direct cytotoxic effects. Over time, hypomethylation can restore expression of previously silenced genes involved in cell differentiation and apoptosis.

Clinical use is most established in myelodysplastic syndromes and related myeloid neoplasms, including chronic myelomonocytic leukemia and some cases of acute myeloid leukemia, particularly in patients who are elderly or not candidates for intensive chemotherapy. Responses vary and are not curative in most cases; treatment typically requires repeated cycles and ongoing monitoring for cytopenias and infections. Side effects commonly include bone marrow suppression, fatigue, nausea, and gastrointestinal symptoms.

The concept of hypomethylation also informs research into epigenetic therapies aimed at correcting abnormal gene regulation across various diseases, not limited to oncology.