Epigenetic drugs: a longstanding story.
In this chapter, the development of decitabine from its synthesis in 1964 to the submission of a registration file in 2004 is reviewed. The proper application of the unique properties of decitabine took quite some time to elucidate. In addition, the practical handling in the clinic was not easy as the prolonged myelosuppression of decitabine made it difficult to determine the preferred dose and schedule. Laboratory studies on DNA methylation and cell differentiation showed possible applications in solid and hematologic malignancies. However, despite many attempts, results in solid tumors have been disappointing thus far. After thorough investigation, decitabine achieved therapeutic application in myelodysplastic syndrome (MDS), in particular in patients with a poor prognosis. Further indications may include acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), hematopoietic stem cell transplantation, sickle cell anemia, and thalassemia. Whereas most drugs are already at the end of their life cycle after 40 years, decitabine is only at the beginning. Its application will broaden with the increase in knowledge of epigenetic mechanisms and their relationship to drug therapy.
de Vos
Dick
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Pharmachemie BV, PO Box 552, 2003 RN Haarlem, The Netherlands. dick.d.vos@pharmachemie.com
D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D002454:Cell Differentiation; D019175:DNA Methylation; D000077209:Decitabine; D015195:Drug Design; D004345:Drug Industry / Q000266:history* / Q000639:trends; D044127:Epigenesis, Genetic; D049673:History, 20th Century; D006801:Humans; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D010597:Pharmacogenetics; D011379:Prognosis; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine