Decreased expression of DNMT1 at the mRNA level following 7 day infusion of the antisense compound MG98 in a phase I study
[This abstract was presented at the recent 16th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. MOGN is rather quiet about this product, but Methylgene continues to claim it is still partnered with MOGN (in the US and with Vernalis in Europe). Don't ask me about the last sentence in the abstract. That's what it says. My guess is that it was some kind of late stage explanatory editing comment that made it all the way into abstract.
European Journal of Cancer Supplements Volume 2, No.8, September 2004, page 132
M. Leslie1, S.A. Coulthard1, E.R. Plummer12, I. Judson3, J.S. de Bono3, L. Vidal3, A. Greystoke3, C. Lee3, A.V. Boddy1, A.H. Calvert12
1University of Newcastle, Northern Institute for Cancer Research, Newcastle upon Tyne, UK
2Newcastle General Hospital, Northern Centre for Cancer Treatment, Newcastle upon Tyne, UK
3Institute for Cancer Research, Royal Marsden Hospital, Sutton, UK
Background: DNA methylation in the promoter region of genes regulates gene expression and is involved in the silencing of tumour suppressor genes in human cancer MG98 is a 20 nucleic acid phosphorothioate antisense oligonucleotide, targeted to the mRNA of DNA methyltransferase DNMT1. In vitro studies have shown that MG98 decreases expression of DNMT1, thus increasing the expression of tumour suppressor and cell-cycle regulating genes such as p16ink4A. Previous Phase I studies of MG98 have indicated that a prolonged infusion of this compound may increase efficacy and provide sustained reductions in DNMT1 expression.
Methods: In the current study, patients received MG98 as a continuous infusion over 7 days, with a break of 7 days between cycles. The starting dose was 100mg/m2/day. Samples of whole blood for the determination of DNMT1 expression in peripheral blood lymphocytes (PBL) were collected before, during and for up to 14 days after each of the first two cycles of administration. mRNA levels for DNMT1 were measured by a validated reverse transcriptase real-time PCR method, using beta-actin as a control for each sample. All analyses were performed in triplicate.
Results: Based on comparison with pre-treatment levels, DNMT1 expression in PBL decreased by between 17 and 69% on cycle one, and between 33 and 85% on cycle 2. The range of pre-treatment DNMT1 expression varied from 0.024 to 2.19 (arbitrary units). In some patients, an apparent rebound effect occurred, with increased DNMT1 expression at the start of cycle 2, compared with the pre-treatment value for cycle 1.
Conclusions: These data indicate that expression of DNMT1 is consistently decreased following MG98 infusion. Further investigations with this compound should include suppression of DNMT1 protein expression and measurement of subsequent changes in DNA methylation in clinical samples. This work was supported by the Vernalis Group of Companies" as well, that would be great (again, late request from our collaborators) |
