Annals of Oncology 14:766-774, 2003
© 2003 European Society for Medical Oncology
Original Paper |
A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly
1 Ottawa Regional Cancer Centre, Ottawa, ON, Canada; 2 Johns Hopkins Oncology Center, Baltimore, MD, USA; 3 National Cancer Institute of Canada Clinical Trials Group, Kingston, ON, Canada; 4 MGI Pharma, Bloomington, MN, USA; 5 MethylGene, Inc., Montreal, QC, Canada
Received 8 January 2003; revised 9 February 2003; accepted 28 February 2003
Background:
Hypermethylation and inactivation of tumor suppressor genes by the enzyme DNA methyltransferase may lead to neoplastic transformation. MG98, a phosphorothioate antisense oligodeoxynucleotide that is a specific inhibitor of mRNA for human DNA methyltransferase 1 (DNMT1), was evaluated in a phase I study.
Patients and methods:
MG98 was given as a 2 h i.v. infusion twice weekly three weeks out of every four to patients with solid tumors. Pharmacokinetic evaluation was performed on days 1 and 15 of cycle 1 and mRNA expression of DNMT1 was measured in peripheral blood mononuclear cells (PBMCs).
Results:
Nineteen patients were entered onto the study. A total of 74 cycles (range 1–18 cycles) were administered at dose levels from 40 to 480 mg/m2. Dose limiting toxicity was seen in two of three patients at 480 mg/m2 and consisted of a constellation of fever, chills, fatigue and, in one case, confusion beginning within 6 h after the first infusion. Other toxic effects included fatigue, anorexia, nausea, vomiting and diarrhea, reversible elevations in transaminases and partial thromboplastin time. Pharmacokinetic evaluation showed Cmax and AUC to be dose proportional with low inter- and intra-patient variability. No consistent changes in DNMT1 mRNA expression were noted in PBMCs. One partial response was documented in a patient with renal cell carcinoma treated at 80 mg/m2.
Conclusions:
The recommended dose of MG98 was 360 mg/m2 given by 2 h infusion twice a week for three weeks out of every four. Phase II trials using this dose and schedule are underway.
Key words: anti-sense oligodeoxynucleotide, DNA methyltransferase I, MG98, phase I
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. J. Stewart, J.-P. Issa, R. Kurzrock, M. I. Nunez, J. Jelinek, D. Hong, Y. Oki, Z. Guo, S. Gupta, and I. I. Wistuba Decitabine Effect on Tumor Global DNA Methylation and Other Parameters in a Phase I Trial in Refractory Solid Tumors and Lymphomas Clin. Cancer Res., June 1, 2009; 15(11): 3881 - 3888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Plummer, L. Vidal, M. Griffin, M. Lesley, J. de Bono, S. Coulthard, J. Sludden, L. L. Siu, E. X. Chen, A. M. Oza, et al. Phase I Study of MG98, an Oligonucleotide Antisense Inhibitor of Human DNA Methyltransferase 1, Given as a 7-Day Infusion in Patients with Advanced Solid Tumors Clin. Cancer Res., May 1, 2009; 15(9): 3177 - 3183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Klisovic, W. Stock, S. Cataland, M. I. Klisovic, S. Liu, W. Blum, M. Green, O. Odenike, L. Godley, J. V. Burgt, et al. A Phase I Biological Study of MG98, an Oligodeoxynucleotide Antisense to DNA Methyltransferase 1, in Patients with High-Risk Myelodysplasia and Acute Myeloid Leukemia Clin. Cancer Res., April 15, 2008; 14(8): 2444 - 2449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hadnagy, R. Beaulieu, and D. Balicki Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics Mol. Cancer Ther., April 1, 2008; 7(4): 740 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Mitra, R. H. Datar, and R. J. Cote Molecular Pathways in Invasive Bladder Cancer: New Insights Into Mechanisms, Progression, and Target Identification J. Clin. Oncol., December 10, 2006; 24(35): 5552 - 5564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Kassis, M. Zhao, J. A. Hong, G. A. Chen, D. M. Nguyen, and D. S. Schrump Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells J. Thorac. Cardiovasc. Surg., February 1, 2006; 131(2): 298 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Miyamoto and T. Ushijima Diagnostic and Therapeutic Applications of Epigenetics Jpn. J. Clin. Oncol., June 1, 2005; 35(6): 293 - 301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Zhang, H. Y. Wang, M. Marzec, P. N. Raghunath, T. Nagasawa, and M. A. Wasik STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes PNAS, May 10, 2005; 102(19): 6948 - 6953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Laird Cancer epigenetics Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R65 - R76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P. Mongan and L. J. Gudas Valproic acid, in combination with all-trans retinoic acid and 5-aza-2'-deoxycytidine, restores expression of silenced RAR{beta}2 in breast cancer cells Mol. Cancer Ther., March 1, 2005; 4(3): 477 - 486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gilbert, S. D. Gore, J. G. Herman, and M. A. Carducci The Clinical Application of Targeting Cancer through Histone Acetylation and Hypomethylation Clin. Cancer Res., July 15, 2004; 10(14): 4589 - 4596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. R. Parulekar and E. A. Eisenhauer Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice J Natl Cancer Inst, July 7, 2004; 96(13): 990 - 997. [Abstract] [Full Text] [PDF]
|
|