title: A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia.
abstract: OBJECTIVE
  Epigenetic silencing via aberrant promoter DNA hypermethylation of normal genes has been described as a leukemogenic mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We hypothesized that MG98, an oligonucleotide antisense to DNA methyltransferase 1 (DNMT1), could reverse malignant phenotypes by down-regulating DNMT1 and inducing reexpression of hypermethylated genes. This phase I study was conducted to determine a biologically effective dose and describe the safety of MG98 in MDS/AML.
  
  
  METHODS
  Twenty-three patients with MDS (n = 11) and AML (n = 12) were enrolled. Biologically effective dose was defined as the dose at which > or =50% of patients experienced >50% reduction in DNMT1 expression with acceptable toxicity. Escalating doses of MG98 were administered according to two schedules (2-hour i.v. bolus followed by 5-day continuous i.v. infusion every 14 days, or 14-day continuous i.v. infusion every 21 days).
  
  
  RESULTS
  DNMT1 down-regulation was observed in 8 patients. However, biologically effective dose was not reached. Reexpression of target genes (P15, WIT1, and ER) was observed in 12 patients but did not correlate with DNMT1 down-regulation. Escalation was stopped due to dose-limiting toxicities (bone pain, nausea, and fever). No objective clinical response was observed. Disease stabilization occurred in 6 (26%) patients.
  
  
  CONCLUSIONS
  No pharmacodynamic or clinical activity was observed at MG98 doses and schedules administered. Despite this, pursuing DNMT1 down-regulation remains a sound approach for targeting aberrant epigenetics in AML/MDS. Future studies with different formulation and/or doses and schedules will be required to ensure efficient MG98 intracellular uptake and fully evaluate its therapeutic potential.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Klisovic
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.forename: Spero
authors.initials: S
authors.lastname: Cataland
authors.forename: Marko I
authors.initials: MI
authors.lastname: Klisovic
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Margaret
authors.initials: M
authors.lastname: Green
authors.forename: Olatoyosi
authors.initials: O
authors.lastname: Odenike
authors.forename: Lucy
authors.initials: L
authors.lastname: Godley
authors.forename: Jennifer Vanden
authors.initials: JV
authors.lastname: Burgt
authors.forename: Emily
authors.initials: E
authors.lastname: Van Laar
authors.forename: Michael
authors.initials: M
authors.lastname: Cullen
authors.forename: A Robert
authors.initials: AR
authors.lastname: Macleod
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Reid
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009838:Oligodeoxyribonucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D013873:Thionucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C483603:MG 98 phosphorothioate antisense oligodeoxynucleotide; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D013873:Thionucleotides; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human