Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: An in vitro and clinical study

Ding,Bingjie; Wang,Zhixiang; Jiang,Xuejie; Li,Xiaodong; Wang,Chunli; Zhong,Qingxiu; Jiang,Ling; Dai,Min; Zhang,Yu; Wei,Qi; Meng,Fanyi

doi:10.3892/mco.2015.605

Palliative chemotherapy followed by methylation inhibitor in high-risk acute myeloid leukemia: An in vitro and clinical study

Authors:
- Bingjie Ding
- Zhixiang Wang
- Xuejie Jiang
- Xiaodong Li
- Chunli Wang
- Qingxiu Zhong
- Ling Jiang
- Min Dai
- Yu Zhang
- Qi Wei
- Fanyi Meng
View Affiliations

Affiliations: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: July 21, 2015 https://doi.org/10.3892/mco.2015.605
Pages: 1139-1144

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Kantarjian H, Ravandi F, O'Brien S, Cortes J, Faderl S, Garcia-Manero G, Jabbour E, Wierda W, Kadia T, Pierce, et al: Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 116:4422–4429. 2010. View Article : Google Scholar : PubMed/NCBI
2	Schiller GJ: When a gold standard is made of tin. Blood. 116:4386–4387. 2010. View Article : Google Scholar : PubMed/NCBI
3	Santini V, Kantarjian HM and Issa JP: Changes in DNA methylation in neoplasia: Pathophysiology and therapeutic implications. Ann Intern Med. 134:573–586. 2001. View Article : Google Scholar : PubMed/NCBI
4	Baylin SB and Ohm JE: Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer. 6:107–116. 2006. View Article : Google Scholar : PubMed/NCBI
5	Jones PA and Takai D: The role of DNA methylation in mammalian epigenetics. Science. 293:1068–1070. 2001. View Article : Google Scholar : PubMed/NCBI
6	Issa JP, Baylin SB and Herman JG: DNA methylation changes in hematologic malignancies: Biologic and clinical implications. Leukemia. 11:(Sul 1). S7–S11. 1997.PubMed/NCBI
7	Melki JR and Clark SJ: DNA methylation changes in leukaemia. Semin Cancer Biol. 12:347–357. 2002. View Article : Google Scholar : PubMed/NCBI
8	Egger G, Liang G, Aparicio A and Jones PA: Epigenetics in human disease and prospects for epigenetic therapy. Nature. 429:457–463. 2004. View Article : Google Scholar : PubMed/NCBI
9	Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, et al: Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 30:2670–2677. 2012. View Article : Google Scholar : PubMed/NCBI
10	Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, Bayar E, Lyons J, Rosenfeld CS, Cortes J, et al: Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 103:1635–1640. 2004. View Article : Google Scholar : PubMed/NCBI
11	Yang AS, Doshi KD, Choi SW, Mason JB, Mannari RK, Gharybian V, Luna R, Rashid A, Shen L, Estecio MR, et al: DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia. Cancer Res. 66:5495–5503. 2006. View Article : Google Scholar : PubMed/NCBI
12	Li K, Hu C, Mei C, Ren Z, Vera JC, Zhuang Z, Jin J and Tong H: Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. J Transl Med. 12:1672014. View Article : Google Scholar : PubMed/NCBI
13	Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M, Grever M, Galm O, Dauses T, Karp JE, et al: Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 66:6361–6369. 2006. View Article : Google Scholar : PubMed/NCBI
14	Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, Vukosavljevic T, Huynh L, Lozanski G, Kefauver C, et al: Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 25:3884–3891. 2007. View Article : Google Scholar : PubMed/NCBI
15	Vardiman JW: The World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues: an overview with emphasis on the myeloid neoplasms. Chem-Biol Interact. 184:16–20. 2010. View Article : Google Scholar : PubMed/NCBI
16	Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, et al: International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 21:4642–4649. 2003. View Article : Google Scholar : PubMed/NCBI
17	Postma TJ and Heimans JJ: Grading chemotherapy-induced peripheral neuropathy. Ann Oncol. 11:509–513. 2000. View Article : Google Scholar : PubMed/NCBI
18	Lübbert M, Suciu S, Baila L, Rüter BH, Platzbecker U, Giagounidis A, Selleslag D, Labar B, Germing U, Salih HR, et al: Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: Final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 29:1987–1996. 2011. View Article : Google Scholar : PubMed/NCBI
19	Leonard SM, Perry T, Woodman CB and Kearns P: Sequential treatment with cytarabine and decitabine has an increased anti-leukemia effect compared to cytarabine alone in xenograft models of childhood acute myeloid leukemia. PLoS One. 9:e874752014. View Article : Google Scholar : PubMed/NCBI
20	Peng CY, Jiang J, Zheng HT and Liu XS: Growth-inhibiting effects of arsenic trioxide plus epigenetic therapeutic agents on leukemia cell lines. Leuk Lymphoma. 51:297–303. 2010. View Article : Google Scholar : PubMed/NCBI
21	Qin T, Youssef EM, Jelinek J, Chen R, Yang AS, Garcia-Manero G and Issa JP: Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res. 13:4225–4232. 2007. View Article : Google Scholar : PubMed/NCBI
22	Zhang YP, Wu WZ and Cui GX: Comparison of clinical efficacy between decitabine combined with CAG regimen and CAG regimen alone in patients with intermediate to high-risk myelodysplastic syndromes. J Exp Hematol. 22:1341–1344. 2014.(In Chinese). PubMed/NCBI
23	Jing Y, Zhu CY, Zhang Q, et al: Clinical efficacy of decitabine combined with modified CAG regimen for relapsed-refractory acute myeloid leukemia with AML1-ETO⁺. J Exp Hematol. 22:1245–1250. 2014.(In Chinese). PubMed/NCBI
24	Benton CB, Thomas DA, Yang H, Ravandi F, Rytting M, O'Brien S, Franklin AR, Borthakur G, Dara S, Kwari M, et al: Safety and clinical activity of 5-aza-2′-deoxycytidine (decitabine) with or without Hyper-CVAD in relapsed/refractory acute lymphocytic leukaemia. Br J Haematol. 167:356–365. 2014. View Article : Google Scholar : PubMed/NCBI
25	Bhatnagar B, Duong VH, Gourdin TS, Tidwell ML, Chen C, Ning Y, Emadi A, Sausville EA and Baer MR: Ten-day decitabine as initial therapy for newly diagnosed patients with acute myeloid leukemia unfit for intensive chemotherapy. Leuk Lymphoma. 55:1533–1537. 2014. View Article : Google Scholar : PubMed/NCBI
26	Mutze K, Langer R, Schumacher F, Becker K, Ott K, Novotny A, Hapfelmeier A, Höfler H and Keller G: DNA methyltransferase 1 as a predictive biomarker and potential therapeutic target for chemotherapy in gastric cancer. Eur J Cancer. 47:1817–1825. 2011. View Article : Google Scholar : PubMed/NCBI
27	Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A and MacLeod AR: DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet. 33:61–65. 2003. View Article : Google Scholar : PubMed/NCBI
28	Daskalakis M, Blagitko-Dorfs N and Hackanson B: Decitabine. Recent Results Cancer Res. 184:131–157. 2010. View Article : Google Scholar : PubMed/NCBI
29	Oki Y, Aoki E and Issa JP: Decitabine - bedside to bench. Crit Rev Oncol Hematol. 61:140–152. 2007. View Article : Google Scholar : PubMed/NCBI