title: Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: Anin vitroand clinical study.
abstract: Decitabine (5-aza-2'-deoxycytidine; DAC) is a well-tolerated alternative to aggressive chemotherapy for leukemia, which induces differentiation and apoptosis of leukemic cells as a DNA hypomethylating agent. The aim of the present study was to investigate the feasibility of DAC sequentially combined with chemotherapy to reverse drug resistance. HL-60/ADR multidrug-resistant leukemia cells cultured in 96-well plates were pretreated with DAC for 72 h; varying concentrations of aclacinomycin (ACLA) were then added to the wells, cell proliferation was tested using the Cell Counting Kit-8 assay, and DNA methyltransferase 1 (DNMT1) protein expression was detected by western blot analysis. Furthermore, we analyzed the therapeutic efficacy in 7 patients with high-risk acute myeloid leukemia (AML) receiving induction therapy with DAC sequentially combined with cytarabine, ACLA and granulocyte-colony stimulating factor (CAG regimen). The proliferation inhibition rate of HL-60/ADR cells treated with DAC at concentrations of 0.5 and 1.0 µmol/l sequentially combined with ACLA was significantly higher compared with that with ACLA alone (P<0.001 for both). DNMT1 expression was significantly repressed following treatment with 1.0 µmol/l DAC. Of the 11 patients, 8 (72.7%) received induction therapy with DAC sequentially combined with CAG agents and achieved complete remission (CR) after 2 cycles of treatment; however, 3 (27.3%) patients did not achieve remission. Myelosuppression was observed in all 11 patients and pulmonary infections developed in 9 patients (81.8%) during the course of the study. At the last follow-up, 7 of the 8 patients who achieved CR remained in remission. The median follow-up was 6 months (range, 3-18 months). Therefore, pretreatment with DAC may increase the sensitivity of HL-60/ADR cells to ACLA via the epigenetic modulation of demethylation and the sequential administration of DAC and CAG regimen appears to be safe and effective for the treatment of patients with high-risk AML.
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Ding
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Xuejie
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China ; Department of Hematology, Kanghua Hospital, Dongguan, Guangdong 523000, P.R. China.
authors.forename: Qingxiu
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Dai
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Y U
authors.initials: YU
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Q I
authors.initials: QI
authors.lastname: Wei
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China ; Department of Hematology, Kanghua Hospital, Dongguan, Guangdong 523000, P.R. China.
authors.forename: Fanyi
authors.initials: F
authors.lastname: Meng
keywords: CAG regimen; HL-60/ADR cells; decitabine; high-risk acute myeloid leukemia