Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies.
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Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H
Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies.
Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463.
- PubMed ID
- 18398832 [ View in PubMed]
- Abstract
Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used decitabine as a classical anticancer drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m(2) per course. At these doses, decitabine was found to be active in leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in cancer and the role of decitabine in epigenetic (hypomethylating) therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at 'optimal biologic' doses that modulate hypomethylation). In these dose schedules of decitabine (100 to 150 mg/m(2) per course), the drug was found to be active with manageable side effects in patients with myelodysplastic syndromes (MDS) and other myeloid tumors. Optimizing dosing schedules of decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that decitabine is an active therapy that alters the natural course of MDS. Combination therapies that augment the epigenetic effect of decitabine will likely improve responses and extend its use for the treatment of other malignancies.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Decitabine DNA Nucleotide Humans YesOther/unknownDetails Decitabine DNA (cytosine-5)-methyltransferase 1 Protein Humans YesInhibitorDetails - Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Decitabine Cytidine deaminase Protein Humans NoSubstrateDetails Decitabine Deoxycytidine kinase Protein Humans YesSubstrateDetails