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PubMed2000

Unnatural enantiomers of 5-azacytidine analogues: syntheses and enzymatic properties.

Although 2'-deoxy-beta-D-5-azacytidine (Decitabine) and beta-D-5-azacytidine display potent antileukemic properties, their therapeutic use is hampered by their sensitivity to nucleophiles and to deamination catalysed by cytidine deaminase. As shown earlier [Shafiee M., Griffon J.-F., Gosselin G., Cambi A., Vincenzetti S., Vita A., Erikson S., Imbach J.-L., Maury G., Biochem. Pharmacol. 56 (1998) 1237-1242], beta-L-enantiomers of cytidine derivatives are resistant to cytidine deaminase. We thus synthesized several 5-azacytosine beta-L-nucleoside analogues to evaluate their enzymatic and biological properties. 2'-Deoxy-beta-L-5-azacytidine (L-Decitabine), beta-L-5-azacytidine, 1-(beta-L-xylo-furanosyl)5-azacytosine, and 1-(2-deoxy-beta-L-threo-pentofuranosyl)5-azacytosine were stereospecifically prepared starting from L-ribose and L-xylose. D- and L-enantiomers of 2'-deoxy-beta-5-azacytidine were weak substrates of human recombinant deoxycytidine kinase (dCK) compared to beta-D-deoxycytidine, whereas both enantiomers of beta-5-azacytidine or the L-xylo-analogues were not substrates of the enzyme. As expected, none of the presently reported derivatives of beta-L-5-azacytidine was a substrate of human recombinant cytidine deaminase (CDA). The prepared compounds were tested for their activity against HIV and HBV and they did not show any significant activity or cytotoxicity. In the case of L-Decitabine, this suggests that the enantioselectivities of concerned enzymes other than dCK and CDA might not be favourable.

Antiviral Agents↗

PubMed2005

The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia.

Cytarabine (ara-C) is the most effective agent for the treatment of acute myeloid leukaemia (AML). Aberrant expression of enzymes involved in the transport/metabolism of ara-C could explain drug resistance. We determined mRNA expression of these factors using quantitative-real-time-PCR in leukemic blasts from children diagnosed with de novo AML. Expression of the inactivating enzyme pyrimidine nucleotidase-I (PN-I) was 1.8-fold lower in FAB-M5 as compared to FAB-M1/2 (P=0.007). In vitro sensitivity to deoxynucleoside analogues was determined using the MTT-assay. Human equilibrative nucleoside transporter-1 (hENT1) mRNA expression and ara-C sensitivity were significantly correlated (rp=-0.46; P=0.001), with three-fold lower hENT1 mRNA levels in resistant patients (P=0.003). hENT1 mRNA expression also seemed to correlate inversely with the LC50 values of cladribine (rp=-0.30; P=0.04), decitabine (rp=-0.29; P=0.04) and gemcitabine (rp=-0.33; P=0.02). Deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA expression seemed to correlate with in vitro sensitivity to gemcitabine (rp=-0.31; P=0.03) and decitabine (rp=0.33; P=0.03), respectively. The dCK/PN-I ratio correlated inversely with LC50 values for gemcitabine (rp=-0.45, P=0.001) and the dCK/CDA ratio seemed to correlate with LC50 values for decitabine (rp=-0.29; 0.04). In conclusion, decreased expression of hENT1, which transports ara-C across the cell membrane, appears to be a major factor in ara-C resistance in childhood AML.

Acute Disease↗

PubMed2002

5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy.

5-Azacytidine was first synthesized almost 40 years ago. It was demonstrated to have a wide range of anti-metabolic activities when tested against cultured cancer cells and to be an effective chemotherapeutic agent for acute myelogenous leukemia. However, because of 5-azacytidine's general toxicity, other nucleoside analogs were favored as therapeutics. The finding that 5-azacytidine was incorporated into DNA and that, when present in DNA, it inhibited DNA methylation, led to widespread use of 5-azacytidine and 5-aza-2'-deoxycytidine (Decitabine) to demonstrate the correlation between loss of methylation in specific gene regions and activation of the associated genes. There is now a revived interest in the use of Decitabine as a therapeutic agent for cancers in which epigenetic silencing of critical regulatory genes has occurred. Here, the current status of our understanding of the mechanism(s) by which 5-azacytosine residues in DNA inhibit DNA methylation is reviewed with an emphasis on the interactions of these residues with bacterial and mammalian DNA (cytosine-C5) methyltransferases. The implications of these mechanistic studies for development of less toxic inhibitors of DNA methylation are discussed.

Antimetabolites, Antineoplastic↗

PubMed2003

Hemoglobinopathies.

The outlook for patients with sickle cell disease has improved steadily during the last two decades. In spite of these improvements, curative therapies are currently available only to a small minority of patients. The main theme of this chapter is to describe new therapeutic options that are at different stages of development that might result in further improvements in the outlook for patients with these disorders. Dr. Joseph DeSimone and his colleagues had previously made the important observation that the hypomethylating agent 5-azacytidine can reverse the switch from adult to fetal hemoglobin in adult baboons. Although similar activity was demonstrated in patients with sickle cell disease and beta-thalassemia, concern about the toxicity of 5-azacytidine prevented its widespread use in these disorders. In Section I, Dr. DeSimone discusses the role of DNA methylation in globin gene regulation and describe recent clinical experience with decitabine (an analogue of 5-azacytidine) in patients with sickle cell disease. These encouraging studies demonstrate significant fetal hemoglobin inducing activity of decitabine in patients who fail to respond to hydroxyurea. In Section II, Dr. George Atweh continues the same theme by describing recent progress in the study of butyrate, another inducer of fetal hemoglobin, in patients with sickle cell disease and beta-thalassemia. The main focus of his section is on the use of a combination of butyrate and hydroxyurea to achieve higher levels of fetal hemoglobin that might be necessary for complete amelioration of the clinical manifestations of these disorders. Dr. Atweh also describes novel laboratory studies that shed new light on the mechanisms of fetal hemoglobin induction by butyrate. In Section III, Dr. Ronald Nagel discusses the different available transgenic sickle mice as experimental models for human sickle cell disease. These experimental models have already had a significant impact on our understanding of the pathophysiology of sickle cell disease. Dr. Nagel describes more recent studies in which transgenic sickle mice provide the first proof of principle that globin gene transfer into hematopoietic stem cells inhibits in vivo sickling and ameliorates the severity of the disease. Although stroke in adult patients with sickle cell disease is not as common as in children, adult hematologists, like their pediatric colleagues, need to make management decisions in adult patients with a stroke or a history of stroke. Dr. Robert Adams has led several large clinical studies that investigated the role of transfusions in the prevention of stroke in children with sickle cell disease. Much less is known, however, about the prevention of first or subsequent strokes in adult patients with sickle cell disease. In Section IV, Dr. Adams provides some general guidelines for the management of adult patients with stroke while carefully distinguishing between recommendations that are evidence-based and those that are anecdotal in nature.

Animals↗

PubMed2003

In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl-positive cell lines.

Imatinib mesylate (Gleevec, formerly STI571) is an effective therapy for all stages of chronic myelogenous leukemia (CML). While responses in chronic-phase CML are generally durable, resistance develops in many patients with advanced disease. We evaluated novel antileukemic agents for their potential to overcome resistance in various imatinib-resistant cell lines. Using cell proliferation assays, we investigated whether different mechanisms of resistance to imatinib would alter the efficacy of arsenic trioxide (As2O3) or 5-aza-2-deoxycytidine (decitabine) alone and in combination with imatinib. Our results indicate that resistance to imatinib induced by Bcr-Abl overexpression or by engineered expression of clinically relevant Bcr-Abl mutants does not induce cross-resistance to As2O3 or decitabine. Combined treatment with these agents and imatinib is beneficial in cell lines that have residual sensitivity to imatinib monotherapy, with synergistic growth inhibition achieved only at doses of imatinib that overcome resistance. In some imatinib-resistant cell lines, combination treatments that use low doses of imatinib lead to antagonism. Apoptosis studies suggest that this can be explained in part by the reduced proapoptotic activity of imatinib in resistant cell lines. These data underline the importance of resistance testing and provide a rational approach for dose-adjusted administration of imatinib when combined with other agents.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia.

We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.

Acetylation↗

PubMed2004

Formation of mitoxantrone adducts in human tumor cells: potentiation by AN-9 and DNA methylation.

The ability of mitoxantrone to form DNA adducts was investigated in a series of human tumor cell lines consisting of human cervical cancer (HeLa), human breast cancer (MCF-7), and human neuroblastoma (IMR-32) cells. The mitoxantrone-resistant human promyelocytic leukemia cell line HL60/MX2 was also compared to the parental cell line HL60 in terms of adduct formation in cellular DNA, RNA, and protein. DNA adduct formation detected using [14C]mitoxantrone as a single agent occurred at very low levels but addition of the formaldehyde-releasing prodrug AN-9 (pivaloyloxymethyl butyrate) increased adduct formation considerably in all cell lines tested. Adduct formation increased when increasing ratios of AN-9 were used, and were observed at maximal levels when AN-9 addition was 4 h after the addition of mitoxantrone. However, low levels of adducts were observed when AN-9 addition was 16 h prior to mitoxantrone. The ability of [14C]mitoxantrone to form adducts with DNA, RNA, and protein was assessed in HL60 cells, and DNA was found to be the major substrate for adduct formation. RNA was also shown to be a good substrate while protein adduct levels were consistently very low. In mitoxantrone-resistant HL60/MX2 cells, DNA adduct levels were approximately fourfold lower. To establish the influence of DNA methylation on the ability of mitoxantrone to form adducts in cells, decitabine was used to reduce DNA methylation levels in cells prior to mitoxantrone treatment. This was clearly shown to influence adduct formation, with increasing decitabine levels leading to a decrease in the level of adducts observed in both IMR-32 and MCF-7 cell lines. Collectively, these results suggest that two major factors that influence the extent of mitoxantrone adduct formation in cells are the availability of formaldehyde and the extent of genomic DNA methylation.

Azacitidine↗

PubMed2005

Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia.

The translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) results in the expression of the fusion protein RUNX1/MTG8, which in turn recruits histone deacetylases (HDAC) to silence RUNX1 target genes [e.g., interleukin-3 (IL-3)]. We previously reported that expression of the RUNX1/MTG8 target gene IL-3 is synergistically restored by the combination of inhibitors of HDACs (i.e., depsipeptide) and DNA methyltransferases (DNMT; i.e., decitabine) in RUNX1/MTG8-positive Kasumi-1 cells. Thus, we hypothesized that DNMT1 is also part of the transcriptional repressor complex recruited by RUNX1/MTG8. By a chromatin immunoprecipitation assay, we identified a RUNX1/MTG8-DNMT1 complex on the IL-3 promoter in Kasumi-1 cells and in primary RUNX1/MTG8-positive AML blasts. The physical association of RUNX1/MTG8 with DNMT1 was shown by coimmunoprecipitation experiments. Furthermore, RUNX1/MTG8 and DNMT1 were concurrently released from the IL-3 promoter by exposure to depsipeptide or stabilized on the promoter by decitabine treatment. Finally, we proved that RUNX1/MTG8 and DNMT1 were functionally interrelated by showing an enhanced repression of IL-3 after coexpression in 293T cells. These results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML.

Acute Disease↗

PubMed1996

New chemotherapeutic agents in acute myeloid leukemia.

Only two classes of chemotherapeutic agents have shown activity in acute myeloid leukemia (AML): ara-C and topoisomerase II reactive agents. Frontline combinations of these agents produce complete response (CR) rates of 70% and long-term event free survival rates of 25%. New agents with different mechanisms of action are being explored. Nucleoside analogs such as chlorodeoxyadenosine (2-CdA) or fludarabine have shown single-agent efficacy and may be synergistic with ara-C. Combination therapy with ara-C and nucleoside analogs have shown promising results both as salvage therapy and in newly diagnosed patients. Combinations of topotecan with ara-C, VP16, and anthracyclines are being pursued, as is testing of other Topo-I inhibitors. Hypomethylating agents (5-azacytidine, decitabine) are showing activity in AML, producing CR rates of 5% to 30% as AML salvage therapy as a single agent, and 40%-60% in combinations. Decitabine may be synergistic with topo I inhibitors, biologic agents, and differentiating agents. Homoharringtonine has modest anti-AML activity, with CR rates of 10% to 30% as salvage therapy. Other classes of agents worthy of continuing investigation are platinum analogs and agents with novel mechanisms of action such as tallimustine.

Acute Disease↗

PubMed2006

Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2'-deoxycytidine retreatment in high-risk myelodysplasia patients.

BACKGROUND: The optimal treatment duration with decitabine (DAC) in patients with myelodysplastic syndromes (MDS) remains a matter of debate. Although at least 2 consolidating courses after best response usually are performed, the response to treatment after disease recurrence has not been systematically studied to date. METHODS: In the current study, the authors report on 22 of 108 patients with MDS (20%) treated with low-dose DAC in 3 Phase II trials who received DAC as retreatment at the time of disease recurrence. RESULTS: According to the International Prognostic Scoring System (IPSS) at the time of initial treatment, 5 of 22 patients (23%) had a score of intermediate-1 (Int-1), 4 patients (18%) had a score of Int-2, and 13 patients (59%) were scored as high-risk. Patients initially received a median of 6 courses of DAC (range, 2 courses-6 courses), which resulted in a complete remission (complete response [CR]) in 12 of the 22 patients (55%). Retreatment with DAC at the time of disease recurrence was initiated at a median of 11 months (range, 3 mos-27 mos) after the last course of initial treatment. With regard to DAC retreatment, patients received a median of 3 courses (range, 1 courses-6 courses), with 10 of 22 patients (45%) responding (1 with a CR and 2 with partial remissions [partial response (PR)]; all 3 patients achieved a CR at the time of initial treatment) and 7 patients demonstrating a hematologic improvement (HI) (at the time of initial treatment there were 2 CRs, 4 PRs, and 1 HI). Twelve of the 22 patients (55%) did not demonstrate any objective responses to retreatment, including 4 patients with primary resistance to the first course of retreatment. The median survival of all patients from the initiation of the first DAC course was 27.5 months (range, 15 mos-50+ mos). The median survival of 43 patients who also had achieved a response to the initial treatment with DAC but who received best supportive care (n = 33 patients) or induction chemotherapy (n = 10 patients) was 18 months (range, 5 mos-72 mos). Second responders to DAC retreatment were found less frequently in the IPSS high-risk group compared with nonresponders (40% vs. 83%). Age, French-American-British classification subtype, serum lactate dehydrogenase level at retreatment, and previous response to DAC were not found to strongly differ between the groups; however, the subgroups were too small to perform a statistical analysis. CONCLUSIONS: Retreatment with DAC was found to result in objective responses in 45% of previously DAC-responsive patients. However, the quality and duration of the second disease remissions were found to be inferior. Therefore, DAC-responsive patients might derive more clinical benefit from continuation of the initial treatment.

Aged↗

PubMed1995

In vitro-induced resistance to the deoxycytidine analogues cytarabine (AraC) and 5-aza-2'-deoxycytidine (DAC) in a rat model for acute myeloid leukemia is mediated by mutations in the deoxycytidine kinase (dck) gene.

The deoxycytidine kinase (dck) gene encodes the enzyme responsible for the metabolic activation of the antileukemic drugs cytosine arabinoside (AraC) and 5-aza-2'-deoxycytidine (decitabine, DAC). The dck locus was analyzed at the chromosomal and the molecular level in a model of rat leukemic cell lines, in which AraC and DAC resistance was induced, that was marked by dck deficiency. At the chromosomal level, karyotype analysis of metaphase spreads revealed the presence of an aberrant 2q + chromosome in the AraC-resistant cell line and a (Xq:11q) translocation in its subclone RA/7. The DAC-resistant lines were identical to the parental RCL/O. Fluorescence in situ hybridization on normal rat fibroblast metaphase spreads localized the rat dck gene to chromosome 14q21-q22, a region that was not involved in any of the observed karyotypic aberrations. Analysis at the molecular level revealed an identical rearrangement of the dck gene in the AraC-resistant cell line RCL/A and its subclone RA/7 that resulted in the absence of dck expression, as assessed by RT-PCR. No genomic rearrangements were observed in a DAC-resistant cell line RCL/D or in its subclone RD/1. However, detection of a single-stranded conformation polymorphism (SSCP) allowed the identification of a single C to G substitution (His to Gln) in the dck cDNA of the DAC-resistant RD/1 clone. The data demonstrate that exposure to AraC and DAC induces a resistant phenotype marked by functional dck deficiency that may be the consequence of mutations occurring in the dck gene.

Animals↗

PubMed2001

Evolving treatment options of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid stem cell disorders characterized by peripheral cytopenias and dysplasia of bone marrow progenitor cells. A clonal evolution can result in progressive bone marrow failure and transformation towards acute myelogenous leukemia. A patient's prognosis as estimated by the International Prognostic Scoring System, age, and co-morbidities have to be considered for the selection of various treatment options. Although supportive care remains standard therapy for low-risk MDS, a number of treatment approaches that aim to improve cytopenia in transfusion-dependent patients are currently under investigation. Among others, immunosuppressive, anticytokine, and antiangiogenic therapy will be discussed. The demethylating agents 5-azacytidine and decitabine are promising for the treatment of elderly patients with high-risk MDS. An increase of the upper age limit for allogeneic stem cell transplantation, the only curative treatment option, by the development of dose-reduced conditioning regimens may have implications for the treatment of MDS patients in the future.

Adult↗

PubMed2002

New drugs in acute myeloid leukemia.

The acute myeloid leukemias (AML) are often fatal disorders with a range of clinical, morphologic, cytogenetic, and molecular features and a consequent need for a diverse array of therapies. This need for tailored therapy for subsets of patients with AML is exemplified in those with acute promyelocytic leukemia, the subject of a separate article in this issue (Tallman and Nabhan). Unfortunately, we tend to examine novel agents in patients with very advanced disease, in which prior therapies have inevitably altered the tumor. Of a myriad of possible exciting novel agents, a few, including PS-341, Genasense (Genta, Berkeley Heights, NJ), decitabine, 5-azacytidine, clofarabine, and troxacitabine, are briefly reviewed with an emphasis on their mechanisms of action from a perspective that suggests possible synergistic therapeutic interventions. With the growing appreciation of the pivotal role of angiogenesis in AML, angiogenesis modulators are a good example of a core class of drugs upon which future noncytotoxic combinations may be built. Those agents targeting vascular endothelial growth factor are also briefly reviewed.

Acute Disease↗

PubMed2006

Strategies for achieving transfusion independence in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a group of complex diseases of the myeloid stem cell that result in chronic cytopenias. In some instances, these disorders may progress to acute myeloid leukemia. Patients with MDS frequently experience chronic, symptomatic anemia, and many become dependent on chronic transfusions of packed red blood cells. However, long-term transfusion dependence has clinical and economic consequences, including a potentially negative impact on patients' quality of life (QOL). Recently, studies have investigated various strategies to reduce or eliminate transfusion needs in MDS patients. Supportive measures with hematopoietic growth factors such as erythropoietin are often less effective in MDS-associated anemia than in anemia from other causes, but some patients may benefit from this approach. Treatment with other agents, such as antithymocyte globulin, azacitidine, decitabine, thalidomide, and lenalidomide, has resulted in transfusion independence in some subsets of MDS patients. Nurses who care for patients with MDS should be aware of the impact of transfusion dependence on the patient's QOL, as well as the benefits and risks of the various other treatment options available to these patients. Such knowledge will enable the nurse to provide accurate, relevant information, so that patients can make informed choices regarding treatment options for MDS.

Anemia↗

PubMed2005

Treatment of myelodysplastic syndrome with a DNA methyltransferase inhibitor: lack of evidence for induction of chromosomal instability.

In several large phase II trials, low-dose treatment with the azanucleoside 5-aza-2'-deoxycytidine (decitabine, DAC) resulted in complete hematologic and cytogenetic responses in 23 and 31% of MDS patients, respectively. The question of induction of chromosomal instability by this demethylating agent was addressed by serial karyotypic analyses. 53/122 DAC-treated patients had all normal metaphases at time of treatment start. In 46/53 patients, sequential cytogenetic analyses were performed. 9/46 patients (20%) acquired clonal chromosomal abnormalities during follow-up (4/9 transient). 8/9 abnormalities were gains or losses of entire chromosomes. The rate and pattern of cytogenetic evolution are thus not higher than in historical MDS cohorts not receiving specific treatment.

Aged↗

PubMed2006

Trisomy 19 as the sole chromosomal abnormality in proliferative chronic myelomonocytic leukemia.

Distinct morphologic and clinical features associated with specific chromosomal abnormalities have been described in subgroups of myelodysplastic syndromes (MDS), which often are losses or gains and only rarely translocations. Among 103 consecutive MDS patients diagnosed and karyotyped at the Albert-Ludwigs University of Freiburg (ALU) between 1993 and 1999, two chronic myelomonocytic leukemias (CMMoL) displayed trisomy 19 (+19) as the sole chromosomal abnormality. Three further CMMoL cases with +19 as the single abnormality, two of which previously reported, were collected from other centers. Four of the five patients presented with leukocytosis and splenomegaly, and an increased number of ringed sideroblasts was observed in two cases. Treatment was low-dose Decitabine (cases 1 and 2), oral steroids (case 3), hydroxyurea (case 4), and daunorubicin/Ara-C (case 5). Transformation to acute myeloid leukemias (AML) occurred in three/five patients (cases 1, 2, and 4) 26, 12, and 22 months after diagnosis of CMMoL, respectively. We conclude that +19 as the sole anomaly is a rare but recurrent change in CMMoL, in particular of the proliferative type. It is at present unclear which gene(s) located on chromosome 19 might have a functional role for the development of this phenotype.

Aged↗

PubMed2002

Somatic recombination: a major genotoxic effect of two pyrimidine antimetabolitic chemotherapeutic drugs in Drosophila melanogaster.

Two deoxycytidine analogues, 1-beta-D-arabinofuranosylcytosine (cytosine arabinoside, citarabine, araC) and 5-aza-2'-deoxycytidine (decitabine, DAC, 5-aza-dC), are the drugs of choice in the treatment of acute myeloid leukaemia. The araC-induced cytotoxicity is a direct result of its interference with nucleic acids synthesis, whereas 5-aza-dC is a potent suppressor of DNA methylation. We employed the standard version of the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster to evaluate the genotoxic potential of these two antimetabolites as a function of exposure concentration. In addition, we determined the relative contributions of mutational and recombinational events to total genotoxicity. The compounds were administered by chronic feeding of 3-day-old larvae. Our results indicate that recombinagenicity is the major genotoxic effect of araC and 5-aza-dC (approximately, 77 and 81%, respectively, recombination). The standardised clone induction frequencies (per mM concentration per cell per cell division) show that 5-aza-dC is 85 times more powerful then araC (inducing approximately 58 mutant clones per 10(5) cells per mM). The high recombinagenic activity of these two drugs suggests that--despite their therapeutic effects against cancer--a question is raised whether these drugs should be considered for adverse effects in cancer chemotherapy.

Animals↗

PubMed2005

Inhibitors of DNA methylation: beyond myelodysplastic syndromes.

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.

Antimetabolites, Antineoplastic↗