Review

Nature Clinical Practice Oncology (2005) 2, S36-S44
doi:10.1038/ncponc0351  
Received 16 August 2005 | Accepted 30 August 2005

Inhibitors of DNA methylation: beyond myelodysplastic syndromes

Pierre Fenaux

Correspondence Service d'Hématologie Clinique, Hôpital Avicenne, Université Paris 13, 125 route de Stalingrad, 93009 Bobigny, France

Email pierre.fenaux@avc.ap-hop-paris.fr

Summary

DNA methyltransferase (DNMT) inhibitors, azacitidine (Vidaza®, Pharmion, Boulder, CO, USA) and decitabine (Dacogen™; SuperGen Inc, Dublin, CA, USA, and MGI Pharma Inc, Bloomington, MN, USA), have had a significant impact on the treatment paradigm of myelodysplastic syndromes (MDSs), previously managed mainly by supportive care and hematopoietic-stem-cell transplantation. The positive clinical experience seen in MDS to date coupled with the persistent challenges faced in the treatment of other hematologic malignancies has served as the impetus for further exploration of the therapeutic value of DNMT inhibitors beyond MDS. In that respect, the majority of data for these agents are in the setting of acute myelogenous leukemia (AML). Experience with these agents in patients with refractory anemia with excess blasts in transformation (reclassified by the World Health Organization as AML) was also reported in the clinical trials submitted to the FDA for approval of azacitidine for MDS. Some use has also been described in chronic myelogenous leukemia and acute lymphocytic leukemia. Further studies are needed to clarify the appropriate dose and the number and duration of cycles in the treatment of leukemias, and to identify ideal candidates for therapy, explore the role of DNMT inhibitors in combination with other agents, especially histone deacetylase inhibitors, delineate differences between the commercially available agents, and establish the long-term safety of these agents. To this end, experience with DNMT inhibitors in hematologic malignancies other than MDS is reviewed in an effort to better understand the therapeutic potential of these agents and to define areas of future exploration in these settings.

Keywords:

azacitidine, acute myeloid leukemia, chronic myeloid leukemia, decitabine, myelodysplastic syndromes

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Introduction

DNA methyltransferase (DNMT) inhibitors azacitidine (5-azacytidine; Vidaza®, Pharmion Corp., Boulder, CO, USA) and decitabine (Dacogen™; SuperGen Inc., Dublin, CA, USA, and MGI Pharma Inc., Minneapolis, MN, USA) have had a significant impact on the treatment paradigm of myelodysplastic syndromes (MDS), previously managed mainly by supportive care and hematopoietic-stem-cell transplantation (HSCT). Although azacitidine was synthesized in the 1960s,1, 2 its clinical value in the treatment of MDS did not become evident until 30 years later, when studies conducted by Silverman and the Cancer and Leukemia Group B (CALGB) showed response rates of 49–60% and the superiority of this agent over BEST SUPPORTIVE CARE.3, 4, 5 On the basis of these data, azacitidine became the first DNMT inhibitor to be approved by the US FDA for the treatment of MDS.6

As the link between methylation and cancer starts to become clearer, the potential benefit of DNMT inhibitors in the treatment of malignancies other than MDS is being increasingly explored.7 Although heterogeneous in their biological mechanisms and clinical progression, most leukemias share the characteristic of being challenging to treat. Despite our growing understanding of the pathophysiology underlying acute leukemias, significant advancements in the treatment of these disorders have not been made in recent years, with a few exceptions such as acute promyelocytic leukemia or Philadelphia-chromosome-positive (Ph+) acute lymphocytic leukemia (ALL). Relapse after induction therapy for acute myelogenous leukemia (AML) continues to be the rule, except in acute promyelocytic leukemia, even in younger patients who have a high likelihood of responding to initial treatment. For younger adult patients (<60 years of age) with AML, 1- and 5-year relative survival rates are generally 50–60% and 25–30%, respectively. Prognosis is poorer in elderly people with AML, because of unfavorable cytogenetics, the presence of multiple comorbidities, and poor performance status.8, 9 Rates of complete remission in older adults (>60 years of age) with AML, who comprise the majority of patients affected with this disease, are only 38–62% when anthracycline-based regimens are used, and the rate of long-term disease-free survival is only 5–15%.10

For chronic myelogenous leukemia (CML), although imatinib represents a significant breakthrough, responses rates and durability of responses with this agent vary depending on disease stage, and resistance or relapse after a short duration of therapy are common findings in the setting of advanced disease.11, 12 On the other hand, HSCT, a potentially curative treatment for CML, carries with it significant morbidity.13

Given the persistent challenges faced in the treatment of leukemias and the positive clinical experience seen with DNMT inhibitors in MDS to date, the most natural setting for further examination of the therapeutic potential of these agents is in leukemias. The majority of information for DNMT inhibitors, outside MDS, is in the setting of AML, which is not surprising in light of the known similarities between MDS and AML in cytogenetic and clinical features.14, 15 Some use of these drugs has also been reported in CML and ALL. Experience with DNMT inhibitors in these hematologic malignancies is reviewed here in order to define areas for future exploration and to develop strategies that effectively incorporate these agents in these settings.

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DNA Methylation in Leukemia

DNA methylation is an epigenetic phenomenon that appears to play an important role in cancer initiation and progression by suppression of genes essential for the control of normal cell growth and differentiation.15, 16, 17 In mammals, DNA methylation is catalyzed primarily by three DNA methyltransferases, DNMT1, DNMT3a, and DNMT3b, and occurs largely at the cytosine residues contained within the dinucleotide sequence cytosine-phosphate diesterguanine (CpG).18, 19 Fully methylated CpG islands (areas of increased density of CpGs) are found exclusively in the promoter regions of selected imprinted autosomal genes and various silenced genes on the inactivated X chromosome of females.15 The exact mechanism by which DNA methylation modulates gene expression in cancer treatment is still being elucidated.

A vast number of genes involved in leukemogenesis have been characterized by CpG island hypermethylation.20 One study found that 19 of 20 bone marrow samples from AML patients were characterized by an abnormal methylation pattern in at least one gene, including the genes coding for calcitonin, estrogen receptor, CDH1, p15, p16, RB1, GSTP1, and HIC1. By contrast, none of eight genes tested was found to be methylated in any of the control samples.21 More specifically, hypermethylation of the p15 tumor-suppressor gene has been observed in at least half of patients with CML, ALL, and AML.22, 23 An abnormal increase in the number of CpG sites of the calcitonin gene was found in 95% of tumor cell DNA samples from patients with AML24 and has been linked to CML transformation into accelerated and blastic phases.25 Hypermethylation of the p21 gene was documented in 41% of bone marrow samples from patients with ALL, and multivariate analysis showed this was an independent risk factor for a poor prognosis.26

Interference with methylation at the level of methyltransferases is currently being explored as a strategy to reactivate quiescent genes that inhibit cancer initiation and progression.27 Azacitidine and decitabine are the first DNMT inhibitors to be described.1 These pyrimidine analogs of cytidine incorporate into RNA and DNA, respectively, and form covalent complexes with DNMTs, leading to depletion of active enzymes (Figure 1). Azacitidine also incorporates into RNA, giving rise to defective messenger and transfer RNA, ultimately resulting in inhibition of protein synthesis.28 Aside from methyltransferase inhibition, these agents are cytotoxic in higher doses, because they directly interfere with DNA synthesis.27, 28

Figure 1 Structure of cytidine, 5-methylcytidine, and methylation inhibitors azacitidine (5-azacytidine) and decitabine (5-aza-2'-deoxycytidine)
Figure 1 : Structure of cytidine, 5-methylcytidine, and methylation inhibitors azacitidine (5-azacytidine) and decitabine (5-aza-2|[prime]|-deoxycytidine) Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

dR, deoxyribose; R, ribose. From reference 70. Used with permission from Nature Publishing Group.

Full figure and legend (12K)Figures & Tables index

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The Past: Early Clinical Studies in AML and CML

Azacitidine

The majority of clinical data for azacitidine in the treatment of leukemia has been as salvage therapy, either as a single agent or in combination with other cytotoxic drugs in the setting of refractory or relapsed AML.29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 It has been studied to a lesser extent in previously untreated AML41, 42, 43 or for the treatment of CML.44, 45 Highly variable response rates (0–58%) with azacitidine have been observed across these clinical settings.

Many of the early findings were most likely attributable to a disparity among reports in the dose of azacitidine studied, baseline disease severity of the study population, and the criteria used to define clinical and hematologic responses. Interpretation of these data has been further limited by various factors relating to study design and methodology. Many of the studies with azacitidine for leukemia treatment have been observational or unblinded in design, and evaluation of the drug's safety and efficacy was not the primary objective. Especially in the early reports, azacitidine was studied at much higher doses than are currently indicated for MDS (75 mg/m2 per day subcutaneously daily for 7 days), and it was found to have serious dose-limiting toxicities, including myelosuppression, that overshadowed its potential utility as an antileukemic agent. In addition, many of the studies evaluated azacitidine in combination with other chemotherapeutic agents, thus hindering the ability to draw definitive conclusions about its contribution to treatment outcomes.

Saiki et al.34 carried out one of the earliest and largest clinical studies with azacitidine as a single agent for the treatment of leukemia. Five different dosage regimens, ranging from 150 mg/m2 for 10 days by continuous intravenous infusion to 750 mg/m2 for 1 day by intermittent intravenous infusion, were compared in adult patients with acute leukemia of all cell types who were in relapse. All patients had received prior aggressive chemotherapy.

Of the 170 patients entered into the study, efficacy end points were fully evaluable in only 120. The overall response rate at the end of the trial was 9.2%, with nine patients achieving complete remission and two achieving partial remission. Lower dose schedules (150 mg/m2 times 10 days and 200 mg/m2 times 7 days) were associated with higher remission rates. However, the difference in outcomes among the various dose schedules was not statistically significant, perhaps because of the low number of patients assigned to each group. Compared with nonresponders, responders to therapy were younger (39.5 versus 31 years) and had a smaller proportion of blasts in the peripheral blood (46% versus 7%). Response to prior treatment did not appear to be a predictor of a positive outcome. Nausea, vomiting, and diarrhea, the most commonly reported adverse events, were observed to the least extent in patients receiving the lower-dose continuous infusions. Prolonged myelosuppression was noted in approximately 7% of patients, and, unlike in other studies with azacitidine, was not dose-related. Coma was reported in 15 patients; however, in 13 of these, an underlying etiology for central nervous system disturbances unrelated to drug toxicity was present. These findings suggested that low-dose continuous infusion schedules of azacitidine might be more effective, with acceptable toxicity, and that further evaluation of azacitidine in combination with other agents is warranted.

Decitabine

Decitabine shares a similar history with azacitidine in that its clinical development relied on the use of very high doses (up to 2,250 mg/m2) administered over short treatment courses.46, 47, 48, 49, 50, 51, 52, 53 Furthermore, its use was limited by excessive and delayed myelosuppression. It was not until the results from more recent phase I and II studies became available that decitabine was recognized as a promising agent for the treatment of MDS,54, 55 AML,55 and CML,55, 56 even in patients who had failed prior therapies. Decitabine has also been successfully used as part of a conditioning regimen prior to HSCT57 and as a single agent with stem-cell reinfusion for relapse after allogeneic progenitor-cell transplant in patients with advanced acute leukemia and CML.58

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The Present: Lower-Dose Strategies in AML and CML

Azacitidine

There have been several studies that have examined azacitidine in leukemia at its currently approved dose for MDS (Table 1).38, 43, 59, 60, 61 Shadduck et al.43 reported on the use of azacitidine in the outpatient setting in 15 adult patients with newly diagnosed AML. Azacitidine was administered at a dose of 75 mg/m2 daily subcutaneously for 7 days every 4 weeks as primary induction therapy to patients who ranged in age from 44 to 80 years and with bone marrow blast counts ranging from 20% to 38%. Eight patients experienced either complete or partial remission in an average of three cycles. Duration of response averaged 8 (range, 6–13) and 3 (range, 2–3) cycles in the groups of patients who achieved complete and partial remission, respectively. Adverse drug events included febrile neutropenia, associated with two deaths, and anorexia necessitating drug discontinuation in one patient.

Table 1 Published studies with low-dose azacitidne and decitabine in acute myelogenous leukemia
Table 1 - Published studies with low-dose azacitidne and decitabine in acute myelogenous leukemia
Full tableFigures & Tables index

In the setting of relapses, Lee et al.38 did not observe any consistent clinical or hematologic response in 11 adult patients with refractory or relapsed AML who were poor candidates for standard cytotoxic therapy. Patients were treated with intravenous azacitidine at a dose of 75 mg/m2 daily continuously for 7 days every 4–6 weeks. These observations were most likely attributable to such pretreatment variables as the severity of their disease (five patients died during the study period or shortly thereafter), advanced age (median, 55 years; range, 36–78 years), and the fact that five courses administered to three patients were unevaluable.

In addition to these studies, over 100 patients with refractory anemia with excess blasts in transformation (RAEBT) or AML were exposed to azacitidine in the clinical trials submitted to the FDA for approval of azacitidine in MDS.3, 4, 62, 63 These data are especially relevant in light of the reclassification by the World Health Organization of RAEBT as AML.64 Among these trials were two phase II studies carried out by Silverman and the CALGB, both of which involved administration of azacitidine 75 mg/m2 daily as a continuous intravenous infusion or subcutaneous bolus infusion for 7 days every 28 days to patients with high-risk MDS.3, 62 Overall response rates ranged from 16% to 48% in elderly patients with RAEBT; the response rate was 17% (3 of 18 patients) in the one report that included AML patients.3, 62, 63

Decitabine

As with azacitidine, insight into the potential efficacy of low-dose decitabine in patients with AML is available from experiences reported in high-risk MDS, including RAEBT. In one of the largest studies to correlate cytogenetic status with response to decitabine therapy in patients with MDS, Wijermans et al.54 reported the highest percentage of responders (14 of 20 patients; 70%) to a 3-day course of decitabine 15 mg/m2 daily in the group of patients with RAEBT. Another valuable finding was the positive correlation between cytogenetic risk category and response rate, with the greatest number of PRs and CRs observed among patients with high-risk cytogenetic abnormalities (e.g. chromosome 7 anomalies, complex cytogenetics).

Lower doses of decitabine were also studied recently by Issa and colleagues55 at the MD Anderson Cancer Center at Houston in a phase I trial involving patients with advanced leukemia or MDS who had failed at least one prior regimen (CML, ALL) or had relapsed after induction (AML, MDS). Analysis of p15 DNA methylation was also carried out in order to quantify the ratio of methylated versus unmethylated polymerase chain reaction product and density of methylation. A total of 48 patients received various doses of decitabine ranging from 5 mg/m2 daily to 20 mg/m2 daily intravenously over 1 h for 10–20 days approximately every 6 weeks.

Overall, objective responses were noted in 16 patients (33%). In 37 patients with AML, 5 (14%) achieved CR, defined as disappearance of all signs and symptoms related to the disease, normalization of peripheral counts, and normal bone marrow morphology. Three patients (8%) achieved partial response (PR). In seven patients with MDS, two (28.5%) achieved complete response (CR) and two achieved PR. In five patients with CML, two achieved CR and two achieved PR. In eight of nine patients, only one cycle of therapy was required to achieve a CR. Although objective responses were achieved with all doses of decitabine, treatment with higher doses (20 mg/m2 for 10 days) and in longer treatment cycles (15 mg/m2 for 20 days) were associated with significantly fewer response rates (45% versus 11%, P = 0.01). The most common nonhematologic adverse effects observed were severe elevation in liver function tests (12%), elevation in serum creatinine (10%), and nausea/vomiting (4%). Febrile episodes were reported in 26 patients (52%), in 18 (69%) of whom they were associated with a documented infection.

The study did not show a correlation between p15 methylation and response to therapy. Samples for 25 patients were available for analysis of p15 methylation. No significant decline in methylation at post-treatment days 5 and 12 with decitabine were noted in any of these patients, regardless of their clinical response. DNA samples from only two of the six patients who achieved a clinical response and had baseline and on-treatment samples available were found to be methylated. Methylation status in these patients remained unchanged at days 5 and 12 after therapy.

Kantarjian et al.56 carried out a phase II study in which decitabine was administered to 130 patients with CMLs in transformation, 123 of whom had Ph+ CML (64 blastic, 51 accelerated, 8 chronic). Patients were initially treated with decitabine 100 mg/m2 over 6 h every 12 h for 5 days every 4–8 weeks. The dose was then reduced to 75 mg/m2 over 6 h every 12 h for 5 days after the first 13 patients experienced severe prolonged myelosuppression, and then to 50 mg/m2 in the remaining 84 patients. A complete hematologic response (CHR) was defined as normalization of peripheral blood counts and differentials with 5% or fewer blasts in the bone marrow for at least 4 weeks. Hematologic improvement was equivalent to CHR, with persistent thrombocytopenia and a few immature cells in the peripheral blood. Partial hematologic response (PHR) was similar to CHR but allowed for persistent palpable splenomegaly and/or few immature cells. A return to the second chronic phase was defined by the disappearance of blastic phase features and a return to chronic phase features.

Overall, 18 patients (28%) in the blastic phase achieved an objective response, including 6 CHR, 7 hematologic improvement (HI), 2 PHR, and 3 second chronic phase. Similarly, 28 patients (55%) in the accelerated phase achieved objective responses, including 12 CHR, 10 PHR, 3 HI, and 3 second chronic phase. In the chronic phase, one patient achieved CHR and four demonstrated PHR. Of the remaining seven patients with Ph- CML, four showed an objective response (two CHR, one PHR, one second chronic phase). The median survival rate was 5 months and 17 months in the blastic and accelerated phase, respectively. A median of three courses was required to achieve the best hematologic response. There was no significant difference in the response rate according to dose of decitabine. The most commonly reported nonhematological adverse effects were drug fever (21%), diarrhea (5%), nausea or emesis (4%), fatigue (2%), cardiac events (2%), and alopecia (2%). Dose-related myelosuppression was significant and was complicated by febrile episodes in 48 patients (37%) and infections in 44 (34%).

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The Future: Areas for Exploration

Decades after having been discovered, the DNMT inhibitors are re-emerging as viable therapeutic modalities, not only for the treatment of MDS, but also potentially for other hematologic malignancies such as AML and CML. The finding that gene silencing by methylation is a feature of a wide variety of tumor types, coupled with the novel and distinct mechanism by which DNMT inhibitors exert their antineoplastic effects, supports further exploration of the therapeutic value of these agents beyond that in MDS alone.

A number of issues will need to be addressed by future studies in order to fully exploit the therapeutic potential of these agents as alternatives or adjunct agents to standard therapies in the setting of leukemia. First, there are dosing considerations. Investigators need to clarify what would be the optimal dose, length of each cycle, and number of cycles to maximize clinical response. With few exceptions, clinical studies with azacitidine and decitabine thus far demonstrate a greater benefit when these agents are used in lower doses, rather than in their maximum tolerated doses, suggesting that the therapeutic potential of these agents lies largely in their hypomethylating effects, and not in direct inhibition of tumor cells, an effect that becomes more pronounced when higher doses are used. Furthermore, it is not yet well defined whether the hypomethylating effects of these agents are time-dependent such that better clinical responses are achieved using treatment cycles longer than the 5- to 7-day cycles now used. Another factor that will be important to take into consideration in determining the optimal schedule of administration of DNMT inhibitors will be cell-cycle parameters of leukemic stem cells. The high sensitivity of cells in the S phase to azacitidine and decitabine suggests that these agents act largely in a cell-cycle-phase-specific manner and may imply that their antileukemic effect is schedule-dependent.32, 65

Another issue to be addressed is that studies are needed to clarify which patient types would be the best candidates, based upon response to previous treatment and cytogenetic status. Phase I/II studies with both azacitidine and decitabine are currently under way in patients with AML, ALL, CML, and CLL (Table 2). In the setting of AML, it will be important to answer the question as to whether the role of DNMT inhibitors should be used as salvage therapy in patients who relapse or are refractory to front-line treatment, or as maintenance therapy in patients who have achieved PR or CR to intensive chemotherapy. The positive responses achieved with DNMT inhibitors in patients with MDS/AML who are older or who display unfavorable cytogenetics should serve as the impetus for future studies focusing on these agents as first-line therapy in patients who are not candidates for standard intensive chemotherapy, because of these factors. Of particular relevance to the treatment of AML will be results from ongoing phase III studies in MDS patients with RAEBT. MDS patients with this subtype have similarities to those with AML in cytogenetic (e.g. presence of complex abnormalities), biologic, and clinical (e.g. poor response to chemotherapy) features. There are also encouraging responses already reported by the CALGB trial studies and Wijermans et al. for these patients.14, 54, 66, 67, 68, 69

Table 2 Examples of ongoing studies with azacitidine and decitabine in leukemia
Table 2 - Examples of ongoing studies with azacitidine and decitabine in leukemia
Full tableFigures & Tables index

A third issue to address is that direct comparisons between DNMT inhibitors are needed before conclusions about the relative efficacy and safety of these two agents can be made.

A further consideration involves combination therapy. Studies using DNMT inhibitors in combination with other agents should be explored further in this setting. Given their unique mechanism of action, the potential for enhanced clinical response when DNMT inhibitors are used in combination with standard therapies, including biological, cytotoxic, and hormonal agents, should be examined. Ongoing phase I/II trials are evaluating the combination of azacitidine with gemtuzumab, azacitidine with etanercept, and decitabine with imatinib. Perhaps of greater importance will be results from studies focusing on the concomitant or sequential use of DNMT inhibitors and histone deacetylase inhibitors, as this strategy is supported by a mechanistic rationale that may translate into a synergistic effect on the reactivation of epigenetically silenced genes that is not possible with other combinations.70

Finally, long-term follow up should be conducted in patients receiving DNMT inhibitors, alone or in combination, to assess critically important disease end points such as duration of remission and mortality, as well as patient safety. One issue that requires clarification is the potential clinical implications of methyltransferase inhibition resulting in the activation of genes that play a role in normal cellular maintenance.71, 72, 73 In addressing such questions, clinicians can better understand the potential of DNMT inhibitors in the management of hematologic malignancies beyond MDS and implement strategies for using these agents in a way that will optimize patient outcomes in this setting.

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References

  1. Piskala A et al. (1964) Nucleic acids components and their analogues. LI. Synthesis of 1-glycosyl derivatives of 5-azauracil and 5-azacytosine. Collect Czech Chem Commun 29: 2060–2076
  2. Hanka LJ et al. (1966) Microbiological production of 5-azacytidine. I. Production and biological activity. Antimicrob Agents Chemother 6: 619–624
  3. Silverman LR et al. (1993) Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia 7 (Suppl 1): 21–29
  4. Silverman LR et al. (2002) Randomized controlled trial of azacitidine in patients with myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol 20: 2429–2440 | Article | PubMed | ISI | ChemPort |
  5. Kornblith AB et al. (2002) Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol 20: 2441–2452 | Article | PubMed | ISI | ChemPort |
  6. Pharmion Corporation. (2004) Vidaza® (azacitidine, injectable, subcutaneous) package insert; Pharmion, Boulder, CO, USA.
  7. Jones PA and Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21: 163–167 | Article | PubMed | ISI | ChemPort |
  8. Behringer B et al. (2003) Prognosis of older patients with acute myeloid leukemia receiving either inducion or noncurative treatment: a single-center retrospective study. Ann Hematol 82: 381–389 | Article |
  9. Leith CP et al. (1997) Acute myeloid leukemia in the elderly: assessment of multi-drug resistance (MDR) and cytogenetics distinguishes biological subgroups with remarkably distinct responses to standard chemotherapy: a Southwest oncology group study. Blood 89: 3323–3329 | PubMed | ISI | ChemPort |
  10. Stone RM et al. Acute myeloid leukemia. In American Society of Hematology Education Program Book: 2004 December 4–7; San Diego, 98–117 (Eds Broudy VC et al.) Washington, DC: American Society of Hematology
  11. Deininger M et al. (2005) The develoment of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105: 2640–2653 | Article | PubMed | ISI | ChemPort |
  12. Hochhaus A et al. (2004) Clinical resistance to imatinib: mechanisms and implications. Hematol Oncol Clin N Am 18: 641–656 | Article | ISI |
  13. Lee SJ et al. (1998) Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16: 2897–2903 | PubMed |
  14. Ghaddar HM et al. (1994) Cytogenetic evolution following the transformation of myelodysplastic syndrome to acute myelogenous leukemia: implications on the overlap between the two disease states. Leukemia 8: 1649–1653
  15. Baylin SB and Herman JG (2000) DNA hypermethylation in tumorigenesis. Trends Genet 16: 168–174 | Article | PubMed | ISI | ChemPort |
  16. Robertson KD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20: 3139–3155 | Article | PubMed | ISI | ChemPort |
  17. Costello JF and Plass C (2001) Methylation matters. J Med Genet 38: 285–303 | Article | PubMed | ISI | ChemPort |
  18. Bestor T et al. (1988) Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J Mol Biol 203: 971–983 | Article | PubMed | ISI | ChemPort |
  19. Okano M et al. (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257 | Article | PubMed | ISI | ChemPort |
  20. Issa J-P et al. (1997) DNA methylation changes in hematologic malignancies: biologic and clinical implications. Leukemia 11 (Suppl 1): 7–11
  21. Melki JR et al. (1999) Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res 59: 3730–3740 | PubMed | ISI | ChemPort |
  22. Herman JG et al. (1996) Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 56: 722–777 | PubMed | ISI | ChemPort |
  23. Nguyen TT et al. (2000) Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications. Blood 95: 2990–2992 | PubMed | ChemPort |
  24. Baylin SB et al. (1987) Hypermethylation of the 5' region of the calcitonin gene is a property of human lymphoid and acute myeloid malignancies. Blood 70: 412–417 | PubMed | ISI | ChemPort |
  25. Malinen T et al. (1991) Acceleration of chronic myeloid leukemia correlates with calcitonin gene hypermethylation. Blood 77: 2435–2440 | PubMed |
  26. Roman-Gomez J et al. (2002) 5' CpG Island hypermethylation is associated with transcription silencing of the p21 CIPI/WAFI/SDI1 gene and confers poor prognosis in acute lymphobalstic leukemia. Blood 99: 2291–2296 | Article | PubMed | ISI | ChemPort |
  27. Christman JK (2002) 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene 21: 5483–5495 | Article | PubMed | ISI | ChemPort |
  28. Von Hoff DD and Slavik M (1977) 5-azacytidine—a new anticancer drug with significant activity in acute myeloblastic leukemia. Adv Pharmacol Chemother 14: 285–326
  29. McCredie KB et al. (1973) Treatment of acute leukemia with 5-azacytidine (NSC-102816). Cancer Chemother Rep 57: 319–323
  30. Tan C et al. (1973) Clinical trial of 5-azacytidine (5-azaCR) [abstract]. Cancer Res 14: 97
  31. Karon M et al. (1973) 5-Azacytidine: a new active agent for the treatment of acute leukemia. Blood 42: 359–365 | PubMed | ChemPort |
  32. Von Hoff DD et al. (1976) 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 85: 237–245
  33. Vogler WR et al. (1976) 5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. Blood 48: 331–337
  34. Saiki JH et al. (1981) Effect of schedule on activity and toxicity of 5-azacytidine in acute leukemia: a Southwest Oncology Group Study. Cancer 47: 1739–1742
  35. Case DC Jr (1982) 5-azacytidine in refractory acute leukemia. Oncology 39: 218–221
  36. Winton EF et al. (1985) Sequentially administered 5-azacitidine and amsacrine in refractory adult acute leukemia: a phase I-II trial of the Southeastern Cancer Study Group. Cancer Treat Rep 69: 807–811 | PubMed | ChemPort |
  37. Hakami N et al. (1987) Combined etoposide and 5-azacitidine in children and adolescents with refractory or relapsed acute nonlymphocytic leukemia: A Pediatric Oncology Group study. J Clin Oncol 5: 1022–1025
  38. Lee EJ et al. (1990) Low dose 5-azacytidine is ineffective for remission induction in patients with acute myeloid leukemia. Leukemia 4: 835–838
  39. Goldberg J et al. (1993) Mitoxantrone and 5-azacytidine for refractory/relapsed ANLL or CML in blast crisis: a leukemia intergroup study. Am J Hematol 43: 286–290 | PubMed |
  40. Steuber CP et al. (1996) Induction treatment of refractory or recurrent childhood acute myeloid leukemia using amsacrine and etoposide with or without azacitidine: a Pediatric Oncology Group randomized phase II study. J Clin Oncol 14: 1521–1525
  41. Oblon D et al. (1984) Long-term follow up of brief, intensive chemotherapy without maintenance therapy for acute myelogenous leukemia (AML): A SECSG pilot study [abstract]. Proc Am Soc Clin Oncol 20: C-748
  42. Grier HE et al. (1992) Intensive sequential chemotherapy for children with acute myelogenous leukemia: VAPA, 80-035, and HI-C-Daze. Leukemia 6 (Suppl 2): 48–51
  43. Shadduck RK et al. (2004) AML induction therapy with outpatient azacitidine [abstract #1800]. In Meeting Abstracts of the American Society of Hematology: 2004 December 5; San Diego http://www.abstracts2view.com/hem_sandiego2004/view.php?nu=HEM4L1_4764] (accessed 28 September 2005); also Blood 104 (Suppl 1): 499a
  44. Schiffer CA et al. (1982) Treatment of the blast crisis of chronic myelogenous leukemia with 5-azacitidine and VP-16-213. Cancer Treat Rep 66: 267–271
  45. Dutcher JP et al. (1992) Phase II study of mitoxantrone and 5-azacytidine for accelerated and blast crisis of chronic myelogenous leukemia: a study of the Eastern Cooperative Oncology Group. Leukemia 6: 770–775
  46. Rivard GE et al. (1981) Phase I study on 5-Aza-2'-deoxycytidine in children with acute leukemia. Leukemia Res 5: 453–462 | Article |
  47. Momparler RL et al. (1985) Clinical trial on 5-aza-2'-deoxycytidine in patients with acute leukemia. Pharmacol Ther 30: 277–286 | PubMed |
  48. Richel DJ et al. (1991) The antileukemic activity of 5-aza-2 deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia. Br J Cancer 64: 144–148 | PubMed |
  49. Petti AC et al. (1993) Pilot study of 5-aza-2'-deoxycytidine (decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. Leukemia 7 (Suppl 1): 36–41
  50. Schwartsmann G et al. (1997) Decitabine (5-Aza-2-deoxycytidine; DAC) plus daunorubicin as a first line treatment in patients with acute myeloid leukemia: preliminary observations. Leukemia 11 (Suppl 1): 28–31
  51. Willemze R et al. (1997) A randomized phase II study on the effects of 5-aza-2' deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group phase II study (06893). Leukemia 11 (Suppl 1): 24–27
  52. Kantarjian HM et al. (1997) Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia 11: 1617–1620 | Article | PubMed |
  53. Sacchi S et al. (1999) Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer 86: 2632–2641 | Article | PubMed | ISI | ChemPort |
  54. Wijermans P et al. (2000) Low-dose 5-aza-2' deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multi-center phase II study in elderly patients. J Clin Oncol 18: 956–962 | PubMed | ISI | ChemPort |
  55. Issa JJ et al. (2004) Phase I study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2' deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103: 1635–1640 | Article | PubMed | ISI | ChemPort |
  56. Kantarjian HM et al. (2003) Results of decitabine (5-aza-2' deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer 98: 522–528 | Article | PubMed | ChemPort |
  57. de Lima M et al. (2003) Long-term follow-up of a phase I study of high-dose decitabine, busulfan, and cyclophosphamide plus allogeneic transplantation for the treatment of patients with leukemias. Cancer 97: 1242–1247 | Article |
  58. Ravandi F et al. (2001) Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study. Bone Marrow Transplant 27: 1221–1225 | Article | PubMed | ChemPort |
  59. Kritz AD et al. (1996) Pilot study of 5-azacytidine (5-AZA) and carboplatin (CBDCA) in patients with relapsed/refractory leukemia. Am J Hematol 5: 117–121 | Article |
  60. Camacho LH et al. (2001) Transcription modulation: a pilot study of sodium phenylbutyrate plus 5-azacytidine [abstract]. Blood 98: 460a
  61. Miller CB et al. (2001) A Phase I dose-descalation trial of combined DNA methyltransferase (MeT)/histone deacetylase (HDAC) inhibition in myeloid malignancies [abstract]. Blood 98: 622a
  62. Silverman LR et al. (1994) Azacitidine in myelodysplastic syndromes: CALGB studies 8421 and 8921 [abstract]. Am Hematol 68: A12
  63. Kaminskas E et al. (2005) Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11: 3604–3608 | Article | PubMed | ChemPort |
  64. Jaffe ES et al. (2001) World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press
  65. Momparler RL et al. (1997) Pharmacological approach for optimization of the dose schedule of 5-Aza-2'-deoxycytidine (Decitabine) for the therapy of leukemia. Leukemia 11: 175–180 | Article | PubMed |
  66. Estey E et al. (1997) Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 15: 2969–2977
  67. Rossi G et al. (2000) Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients. Leukemia 14: 636–641 | Article | PubMed |
  68. Parker JE et al. (2000) The role of apoptosis, proliferation, and the Bcl-2 related proteins in myelodysplastic syndromes and acute myeloid leukemias secondary to MDS. Blood 96: 3932–3938 | PubMed | ISI | ChemPort |
  69. Vardiman JW et al. (2002) The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100: 2292–2302 | Article | PubMed | ISI | ChemPort |
  70. Claus R et al. (2003) Epigenetic targets in hematopoietic malignancies. Oncogene 22: 6489–6496 | Article | PubMed | ISI | ChemPort |
  71. Chen RZ et al. (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395: 89–93 | Article | PubMed | ISI | ChemPort |
  72. Sato N et al. (2003) Effects of 5-aza-2'-deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasiveness. J Natl Cancer Inst 95: 327–330 | PubMed | ChemPort |
  73. Eden A et al. (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300: 455 | Article | PubMed | ISI | ChemPort |
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Competing interests

Prof Pierre Fenaux is a regular consultant of Pharmion Corp.

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