A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia.
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.
Klisovic
Rebecca B
RB
Division of Hematology and Oncology, Department of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Stock
Wendy
W
Cataland
Spero
S
Klisovic
Marko I
MI
Liu
Shujun
S
Blum
William
W
Green
Margaret
M
Odenike
Olatoyosi
O
Godley
Lucy
L
Burgt
Jennifer Vanden
JV
Van Laar
Emily
E
Cullen
Michael
M
Macleod
A Robert
AR
Besterman
Jeffrey M
JM
Reid
Gregory K
GK
Byrd
John C
JC
Marcucci
Guido
G
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*
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