Use of DNA methylation inhibitors for chemotherapy and chemoprevention of cancer.

摘要

Aberrant DNA methylation is a common feature of cancer, which has been targeted for pharmacologic intervention because of its reversible nature. Nucleoside analogs such as 5-azacytidine, 5-aza-2'-deoxycytidine, and zebularine are mechanism-based inhibitors of DNA methylation that are incorporated into the DNA during replication and deplete the DNA methyltransferase enzymes. 5-Azacytidine and 5-aza-2'-deoxycytidine are extremely potent inhibitors and may be ideal for use in chemotherapy of cancer. Delivery of these inhibitors has been facilitated with the use of short oligonucleotides that prevent enzymatic degradation. On the other hand, zebularine, a more stable and less toxic surrogate of the other two compounds may be best utilized as a chemopreventive agent. Chronic oral administration of zebularine in a murine colon cancer model highlighted its low toxicity and gender- and tissue-specific action against DNA methylation.