Pharmacodynamic analysis of the DNA methyltransferase inhibitor decitabine in patient tissues
Başlık:
Pharmacodynamic analysis of the DNA methyltransferase inhibitor decitabine in patient tissues
Yazar:
Appleton, Kim Joanne, author.
ISBN:
9780438061446
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (212 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Advisors: Bob Brown.
Özet:
Aberrant DNA methylation is one of the hallmarks of cancer cells and almost all human cancer types show altered patterns of methylation. Hypermethylation of the CpG islands found in gene promoters has been shown to be associated with transcriptional inactivation of the associated gene and has been observed to occur in several genes that are involved in tumour growth and development, including tumour suppressor genes. The pharmacodynamic effects of the DNA methyltransferase inhibitor 2'deoxy-5-azacytidine (Decitabine) have been studied in a Phase I trial of patients with advanced solid tumours where Decitabine was given as a 6 hour infusion in combination with Carboplatin given as a 1 hour intravenous infusion. Decitabine has previously been used as a single agent in the treatment of haematological malignancies. However, it has also been shown that decitabine can resensitise drug resistant tumour xenografts suggesting its potential in combination with cytotoxic chemotherapies. Global 5-methyl-2'deoxycytidine levels were examined in peripheral blood mononuclear cells (PMN) DNA of patients by HPLC. MAGE1A CpG-island methylation was analysed in PMN and buccal smear DNA by Methylation Specific PCR. In order to fulfil the EU Clinical Trials Directive issued in May 2001, the examination and analysis of these samples was performed in compliance with Good Clinical and Laboratory Practice (GCLP) regulations. Therefore, these assays were validated prior to patient sample analysis. Patient samples showed dose dependent decreases in levels of 5-methyl-2'deoxycytidine in PMN DNA following decitabine treatment. Maximal mean decreases of 33% (n=3), 36% (n=6) and 49.5% (n=3) were observed for 45mg/m2, 90mg/m2 and 135mg/m2 decitabine respectively from 10 to 12 days following decitabine treatment. There is a good correlation between peak plasma levels of decitabine and AAC (area above the curve) for demethylation in PMN DNA. Demethylation was also seen in the promoter of the MAGE 1A gene following methylation specific PCR of PMN and buccal mucosa DNA. This was maximal 8 to 12 days after decitabine treatment. Pyrosequencing of bisulphite modified DNA showed an increase in the amount of unmethylated cytidines present at individual CpG sites within the MAGE1A promoter in PMN DNA and to a lesser extent in tumour biopsies following decitabine treatment. Gene re-expression of a previously hypermethylated gene was also evident. Levels of foetal haemoglobin in lymphocytes increase 8-12 days after treatment of patients with 90mg/m2 decitabine and have returned to approximate starting levels by day 15. In subsequent cycles of treatment there is apparent accumulation of HbF levels, suggesting that repeat treatment of patients with decitabine is more effective than a single treatment in inducing HbF expression The amount of demethylation observed in PMNs of patients is greater than demethylation observed in PMNs of mice that have concomitant chemosensitisation of xenografts.. Thus it can be said that this therapy could be used to potentially re-sensitise tumours which have become resistant to traditional therapies because of methylation and subsequent silencing of important genes.
Notlar:
School code: 0547
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(684879.1) | 684879-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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