RESUMO
Decitabine (DAC) is a small molecule nucleotide analog that is incorporated into DNA and traps human DNA methyltransferases. Although initially developed as a cytotoxic agent, low-dose DAC is enjoying a revival as a specific inhibitor of hypermethylation in cancer. DAC has activity in several hematological diseases, especially myelodysplastic syndrome, chronic myelogenous leukemia and acute myeloid leukemia. Clinical and preclinical advances are presented in this review.
Assuntos
Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Metilases de Modificação do DNA/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Animais , Azacitidina/metabolismo , Azacitidina/farmacologia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Metilases de Modificação do DNA/metabolismo , Decitabina , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Neoplasias Hematológicas/enzimologia , HumanosRESUMO
Decitabine (5-aza-2'-deoxycytidine) inhibits DNA methylation and has dual effects on neoplastic cells, including the reactivation of silenced genes and differentiation at low doses and cytotoxicity at high doses. We evaluated, in a phase 1 study, low-dose prolonged exposure schedules of decitabine in relapsed/refractory leukemias. Patient cohorts received decitabine at 5, 10, 15, or 20 mg/m2 intravenously over one hour daily, 5 days a week for 2 consecutive weeks, doses 5- to approximately 30-fold lower than the maximum tolerated dose (MTD). There were 2 groups that also received 15 mg/m2 daily for 15 or 20 days. A total of 50 patients were treated (44 with acute myelogenous leukemia [AML]/myelodysplasia [MDS], 5 with chronic myelogenous leukemia [CML], and 1 with acute lymphocytic leukemia [ALL]), and the drug was well tolerated at all dose levels, with myelosuppression being the major side effect. Responses were seen at all dose levels. However, the dose of 15 mg/m2 for 10 days appeared to induce the most responses (11 of 17 or 65%), with fewer responses seen when the dose was escalated or prolonged (2 of 19 or 11%). There was no correlation between P15 methylation at baseline or after therapy and response to decitabine. We conclude that decitabine is effective in myeloid malignancies, and low doses are as or more effective than higher doses.