Decitabine in Myelodysplastic Syndromes

DRUG PROFILE Decitabine in myelodysplastic syndromes Elias Jabbour, Decitabine (5-aza-2’-deoxycytidine), a cytosine analog, inhibits DNA methylation and has Hagop M Kantarjian, dual effects on neoplastic cells, including the reactivation of silenced genes and Guillermo Garcia-Manero & differentiation at low doses, and cytotoxicity at high doses. Decitabine has promising Jean-Pierre J Issa† clinical efficacy in the treatment of myelodysplastic syndromes (a heterogeneous group of bone marrow malignancies), with evidence of target modulation (hypomethylation) and a †Author for correspondence The University of Texas, favorable toxicity profile. Optimal dosing schedules of decitabine in myelodysplastic Department of Leukemia, syndrome are those that maximize hypomethylation (low dose, high dose intensity, Unit 428, multiple cycles). However, the molecular mechanisms of in vivo response to decitabine are MD Anderson Cancer Center, 1515 Holcombe Blvd, still unclear. Combination therapies that augment decitabine’s epigenetic effect, or take Houston, Texas 77030, USA advantage of gene activation, will likely improve clinical responses and may extend its use Tel.: +1 713 145 2260 to the treatment of other malignancies. Fax: +1 713 794 4297 [email protected] The development of new therapeutic strategies disease progression. The cyclin-dependent for the myelodysplastic syndrome (MDS) has kinase inhibitor p15 was described as a frequent been the result of extensive understanding of the target of aberrant methylation in MDS and its pathobiology of the disease. Therapeutics target- inactivation is associated with an increased risk ing chromatin structure, angiogenesis and the of progression to acute myeloid leukemia microenvironment that nurtures the MDS phe- (AML) [7]. Other similar genes were also notype have demonstrated significant activity described and their aberrant methylation was and offer an opportunity to alter the natural his- associated with resistance to chemotherapy [8,9]. tory of the disease [1]. Chromatin remodeling is a Azacitidine (5-azacitidine) and decitabine (5- powerful mechanism of regulating gene expres- aza-2’-deoxycytidine) are cytosine analogs synthe- sion and protein function [2]. In extreme states, sized in the 1960s with demonstrated in vitro anti- chromatin remodeling can permanently repress leukemic activity [5]. Azacitidine is converted the expression of a gene – a situation termed epi- intracellulary to decitabine. Decitabine in turn is genetic silencing. Such silencing is exploited by converted to decitabine triphosphate which incor- cancers to fully express the malignant porates into DNA, binds to and depletes DNA phenotype [3]. Evidence supporting a role of epi- methyltransferase protein levels, and results in rep- genetic gene silencing in tumorigenesis stems lication-dependent DNA hypomethylation [10,11]. from studies revealing a large number of genes Decitabine appears to have dual effects on treated that are silenced by aberrant DNA methylation cells. At high doses, it causes DNA synthesis arrest in different types of cancers – many of which are and apoptosis due to DNA adducts [12]. At low involved in the control of cell-cycle progression, doses, cells survive but change their gene expression apoptosis, tissue invasion and genomic stability. profile to favor differentiation, reduced prolifera- DNA methylation is remarkably altered in tion, and/or increased apoptosis [10,13]. This dual most malignancies, with concomitant global activity reawakened interest in hypomethylating and localized hypermethylation [4]. This agents as both antineoplastics and biologic response increased methylation affects mainly CpG modifiers [5]. Azacitidine was recently approved by islands located in regulatory regions such as gene the US Food and Drug Administration (FDA) for Keywords: decitabine, promoters, and often suppresses gene expression the treatment of MDS and has been extensively epigenetic therapy, permanently, providing cancers with an alterna- reviewed [14–16]. This article focuses on the role of methylation, tive to mutations or deletions for the inactiva- decitabine in the treatment of MDS. myelodysplastic syndrome tion of tumor-suppressor and other critical genes. Indeed, leukemias and MDS are charac- Mechanism of action terized by the hypermethylation and silencing of Decitabine is a deoxycytidine analog which is multiple genes [5,6]. This process can occur early phosphorylated and incorporated into DNA. Future Drugs Ltd in the disease course and is also associated with Once incorporated, it covalently binds to DNA 10.1586/14750708.2.6.835 © 2005 Future Drugs Ltd ISSN 1475-0708 Therapy (2005) 2(6), 835-842 835 DRUG PROFILE – Jabbour, Kantarjian, Garcia-Manero & Issa methyltransferases and traps the enzymes to of decitabine produces a loss of clonogenicity in DNA, acting as an irreversible inhibitor of their the same range of cells in the S phase (30–50%). enzymatic activity. As a result, decitabine pro- A longer exposure time of 24 h showed a mark- duces marked DNA hypomethylation in vitro edly higher antineoplastic activity, with greater and in vivo [17]. Through hypomethylation than 95% loss of clonogenicity, using a dose of induction, decitabine restores silenced gene 1µm[25]. In plasma and cerebrospinal fluid (CSF) expression. The precise molecular mechanism of pharmacokinetic assays, the half-life of decitabine this phenomenon is increasingly being deci- was between 39 and 144 min depending on the phered. A number of studies have illustrated a animal model, and decitabine concentrations in cascade of biochemical events triggered by pro- the CSF were 27 to 58% of the plateau plasma moter DNA methylation that involves initial concentration [11]. However, the intracellular half- DNA binding proteins, which attract histone life of decitabine, particularly after DNA incorpo- deacetylases and histone methylases that eventu- ration, is not known and maybe considerably ally modify histones into a silenced chromatin higher. Oral administration of decitabine is not state [18,19]. Moreover, a feedback loop appears to optimal due to rapid decomposition of this analog be evident between DNA methylation and his- in acid [11]. tone methylation whereby each of these biochemical modifications at a given gene triggers Clinical trials the other, thus creating a self-reinforcing silenc- Phase I studies ing loop [19]. This silencing loop is interrupted by Decitabine has been in clinical trials for over two decitabine. Thus, treatment of neoplastic cell decades [5]. The original studies were classical lines with decitabine has been shown to induce Phase I trials which identified the maximally toler- hypomethylation and reverse the silenced histone ated dose (MTD) as 1500 to 2250 mg/m2 [26,27]. code rapidly at tumor-suppressor gene loci [20–22]. The dose-limiting toxicity was primarily hemato- This dual effect (hypomethylation–histone logic. Phase II studies were disappointing in solid changes) explains the superiority of decitabine on tumors [28], but more promising in AML, MDS gene expression activation, compared with the and CML. histone-deacetylase inhibitors [23]. Decitabine also The first clinical studies of decitabine in has significant effects on the expression of genes hematologic malignancies used 1500 to that are not silenced by CpG island methylation. 2500 mg/m2/course. Response rates with decit- Decitabine induces the expression of p21, a gene abine as a single agent or in combination with that shows no DNA hypermethylation in other therapies were 30 to 60% [13,26,27,29–31] cancer [24]. At a molecular level, the effects of (Table 1). Despite promising activity, high-dose decitabine on the histone code are not limited to decitabine regimens were not pursued because of genes showing silencing by promoter-associated delayed and prolonged myelosuppression. At methylation [22], for example the histone H3- these doses, the drug is likely to be working as a lysine 9 acetylation:methylation ratio was signifi- cytotoxic cytosine nucleoside analog, and its cantly increased by decitabine treatment of neo- superiority in that regard to cytarabine was not plastic cells at genes showing no DNA clear. Decitabine at a lower dose schedule hypermethylation. This silencing-independent (15 mg/m2 three times a day for 3 days) was activity of decitabine remains incompletely reported to have encouraging activity in understood. Some of the changes could be reac- MDS [32]. An even lower dose (0.15 mg/kg/day tive, related to the stresses of exposing cells to a over 1 h for 10 days) was reported to have bio- potentially cytotoxic agent. Nevertheless, the ulti- logical efficacy in reactivating hemoglobin F in mate antineoplastic mechanism of action for patients with sickle cell disease, with relatively decitabine could be very pleiotropic and deserves little toxicity [33]. These observations, combined further investigation. with the short half-life of the drug and its abso- lute requirement for DNA synthesis for activity, Pharmacology & pharmacokinetics led to a novel Phase I trial of decitabine in Given that the antineoplastic action of decitabine patients with relapsed or refractory leukemia, is a result of its incorporation into newly synthe- testing low-dose longer exposure schedules with sized DNA, it is an S phase-specific agent [11]. At the intent of finding an ‘optimal dose’ for low doses, it does not block cell cycle progression responses other than the MTD [34]. A total of 50 of G1-phase cells into the S phase. In

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