Clinical development of decitabine as a prototype for an epigenetic drug program.
This review highlights decitabine as a prototype epigenetic modifying drug to show how the clinical development of epigenetic agents differs from that of traditional cytotoxic chemotherapies. Decitabine, a cytosine analogue, is cytotoxic at high doses but has selective DNA demethylating activity at low doses. The focus of current decitabine investigations is twofold: to elucidate all of the mechanisms of action and to determine the optimal dose, schedule, and concomitant therapies. New phase I trials have identified a "biologically effective dose," which is 1 to 2 logs lower than the cytotoxic dose. A clinical development program with low-dose decitabine in malignant diseases is focused on myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). A phase III trial in MDS showed objective responses (complete [CR] plus partial [PR] remission) and longer median time to progression to AML or death with decitabine than with supportive care alone. The optimal use of decitabine may be in combination with other agents that promote gene expression, namely, histone deacetylase (HDAC) inhibitors. Optimized decitabine doses and combinations with other epigenetic therapies that can be used at minimally toxic doses provide potentially safer therapeutic options and introduce novel combination therapies.
Rosenfeld
Craig S
CS
crosenfe@swbell.net
D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002986:Clinical Trials as Topic; D018736:DNA Adducts; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D000077209:Decitabine; D001374:Azacitidine