Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks

Invest New Drugs. 2003 Feb;21(1):85-97. doi: 10.1023/a:1022976528441.

Abstract

Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks.

Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45.

Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m2/day. The dose level of 80 mg/m2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed.

Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
  • DNA (Cytosine-5-)-Methyltransferases / blood
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Fetal Hemoglobin / analysis
  • Humans
  • Infusions, Intravenous
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Oligodeoxyribonucleotides / administration & dosage
  • Oligodeoxyribonucleotides / blood
  • Oligodeoxyribonucleotides / pharmacology*
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / blood
  • Oligonucleotides, Antisense / pharmacology*
  • Proteins / analysis
  • Proteins / genetics
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / blood
  • Thionucleotides
  • Time Factors
  • Treatment Outcome
  • Up-Regulation
  • Vimentin / blood
  • Vimentin / genetics

Substances

  • GADD45 protein
  • Intracellular Signaling Peptides and Proteins
  • MG 98 phosphorothioate antisense oligodeoxynucleotide
  • Oligodeoxyribonucleotides
  • Oligonucleotides, Antisense
  • Proteins
  • RNA, Messenger
  • Thionucleotides
  • Vimentin
  • Fetal Hemoglobin
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human