A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly

Stewart, David J.; Donehower, Ross C.; Eisenhauer, Elizabeth; Wainman, Nancy; Shah, Ajit; Bonfils, Claire; MacLeod, A. Robert; Besterman, Jeffrey M.; Reid, Gregory K.

doi:10.1093/annonc/mdg216

Cited by 86 publications

(46 citation statements)

References 16 publications

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“…It has been reported that higher expression of methyltransferases was associated with methylation of p16 and p15 genes in HCC [29] . It has been noted that either the inhibitors of methyltransferase, such as 5-aza-2'-deoxycytidine and tea-polyphenol (-)-epigallocatechin-3-gallate or antisense inhibitors of DNA methyltransferases, reactivated silenced tumor suppressor genes and inhibited the growth of cancer cells [30][31][32][33] . Thus, methylation of 5'CpG islands of p16 and p15 genes might be an early event in hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis

Qin¹,

Liu²,

Li³

et al. 2004

WJG

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AIM:To study the significance of p16 and p15 transcription suppression with hypermethylation of their genes' 5'CpG islands during human hepatocellular carcinogenesis. METHODS:The mRNA expression levels of p16 and p15 genes were evaluated in cancerous, para-cancerous and noncancerous tissues of 20 HCC, 3 normal liver tissues from 3 accidentally died healthy adults using semi-quantitatively Northern blot. The methylation status was also assessed with methylation specific PCR. RESULTS: p16 mRNA expression level was decreased in the cancerous tissues in 60% (12/20) of HCC patients, of which 2 cases had no p16 mRNA detected, 5 cases (25%) displayed variation in the order of cancerous

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Section: Discussionmentioning

confidence: 99%

Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis

Qin¹,

Liu²,

Li³

et al. 2004

WJG

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“…Despite differences in the therapeutic schedules in terms of mode of administration and dosage, both treatment protocols resulted in significant side effects, such as transaminitis, anemia, weakness, fever, nausea, and anorexia. 100,101 The best-tolerated protocol was chosen for phase II studies but, unfortunately, did not show any antitumoral activity in patients with metastatic renal carcinoma. 102 In a recent phase I trial, MG98 has been also tested for the treatment of patients with high-risk MDS and AML.…”

Section: Dnmt Silencingmentioning

confidence: 99%

DNA Demethylating Antineoplastic Strategies: A Comparative Point of View

et al. 2010

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IntroductionEpigenetics is the study of somatically heritable and reversible modifications of genome functions (gene expression and genomic stability) not involving changes in DNA sequence. DNA methylation, together with histone posttranslational modifications (PTMs), represents the most characterized epigenetic modification and is known to participate in the regulation of gene expression by modifying the chromatin structure and, consequently, the accessibility of transcription factors to regulatory regions of genes. Aberrant epigenetic patterns are involved at early stages of cancer initiation and, altering both global gene expression and genomic stability, strongly contribute to cancer progression. 1 DNA methylation involves the covalent addition of a methyl group (-CH3) to the C-5 position of cytosine, mostly in the context of the CpG dinucleotide. This chemical reaction is catalyzed by enzymes belonging to the DNA methyltransferase family (DNMTs). DNMT1 is predominantly responsible for maintaining the preexistent methylation pattern during DNA replication, whereas DNMT3a and DNMT3b are required for de novo DNA methylation. 2,3 CpG dinucleotides are clustered in regions, named CpGislands, present in almost 60% of all gene promoters. 4 DNMT activity regulates global gene expression by hypermethylation of promoter CpG-islands and, as recently shown, of regulatory sequences near the promoter (CpG island shores), thus causing gene silencing. Not surprisingly, the DNA methylation pattern is altered in cancer. Paradoxically, tumor cells exhibit global genome hypomethylation and increased levels of DNMT1 expression at the same time. Moreover, both DNA hypo-and hypermethylation occur at specific gene loci, leading to the overexpression of proto-oncogenes and the silencing of tumor suppressor genes, respectively. These phenomena are thought to be promoting factors of cellular transformation. 5,6 Evidence regarding the involvement of DNA methylation in tumorigenesis gave rise to the development of new therapeutic strategies that target this modification. In the past few years, many drugs have been proposed. Some have already been approved for clinical use, and many others are still under evaluation. In this review, we focus on antineoplastic strategies affecting DNA methylation, with particular attention to their mechanism of action and the molecular pathways involved. In addition, we compare novel approaches, such as the use of nonnucleoside inhibitors and DNMT silencing with azanucleoside administration, the only demethylating strategy approved for clinical therapy. Despite the involvement of genetic alterations in neoplastic cell transformation, it is increasingly evident that abnormal epigenetic patterns, such as those affecting DNA methylation and histone posttranslational modifications (PTMs), play an essential role in the early stages of tumor development. This finding, together with the evidence that epigenetic changes are reversible, enabled the development of new antineoplastic therapeutic approaches known as...

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“…Indeed a phase I clinical trial of this human DNA methyltransferase ASO been completed and phase II trials are in progress to explore this possibility. 19 …”

Section: Inhibition Of Dnmt1 Induces Re-expression Of Er In Er-negatimentioning

confidence: 99%

Specific Inhibition of DNMT1 by Antisense Oligonucleotides Induces Re-expression of Estrogen Receptor a (ER) in ER-negative Human Breast Cancer Cell Lines

Yan¹,

Nass²,

Smith³

et al. 2003

Cancer Biology & Therapy

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Recent studies have shown that changes in epigenetic regulation, such as DNA methylation and histone acetylation, are associated with silencing of the estrogen receptor α (ER) gene in ER-negative human breast cancer cells. Treatment of these cells with the general DNMT inhibitor, 5-aza-2'deoxycytidine, led to reactivation of functional ER protein. This study addresses the hypothesis that specific inhibition of the maintenance DNA methyltransferase, DNMT1, by antisense oligonucleotides (DNMT1 ASO) is sufficient to re-express the ER gene in ER-negative human breast cancer cell lines. MDA-MB-231 and Hs578t cells were transfected with 100 nM and 150 nM DNMT1 ASO respectively for three consecutive days and evidence of DNMT1 downregulation and functional ER re-expression was sought. Significant growth reduction was observed within 48 hr and persisted after 96 hr. DNMT1 expression was blocked after exposure to DNMT1 ASO as detected by RT-PCR, Western blot and enzymatic assay whereas a mutant DNMT1 ASO had little effect. This was associated with enhanced ER mRNA and protein expression and restoration of estrogen responsiveness in MDA-MB-231 cells as demonstrated by the ability of the induced ER protein to elicit ERE-regulated reporter activity from a luciferase reporter construct. Methylation specific PCR showed that the ER CpG island was minimally demethylated, suggesting that other epigenetic events, introduced by specific DNMT1 inhibition, might also be involved in ER re-expression. Our results suggest that specific inhibition of DNMT1 expression alone is sufficient to re-express ERa in human breast cancer cell lines.

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A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly

Abstract: The recommended dose of MG98 was 360 mg/m(2) 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.

Cited by 86 publications

References 16 publications

Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis

Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis

DNA Demethylating Antineoplastic Strategies: A Comparative Point of View

Specific Inhibition of DNMT1 by Antisense Oligonucleotides Induces Re-expression of Estrogen Receptor a (ER) in ER-negative Human Breast Cancer Cell Lines

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