Aberrant hypermethylation of CpG islands within promoter regions of DNA modifies expression of genes involved in diverse cellular processes that impact tumor cell growth and behavior. Recent studies have shown that promoter methylation is important in silencing DNA repair enzymes, and inducing expression of drug sensitivity or resistance phenotypes. For example, cancer cell sensitivity to interferon-a is believed to be regulated by promoter methylation of key genes. The nucleoside analogue 5-aza-2'- deoxycytidine (decitabine) is a potent pharmacological inhibitor of DNA methylation in vitro. Decitabine-induced DNA hypomethylation, gene reactivation, and effects on cell function require incorporation into DNA followed by several cellular division cycles in vitro. We previously performed a phase I trial of decitabine, which established that 2mg/m2/day, given as a 168h continuous i.v. infusion resulted in significantly decreased MAGE-1promoter-specific and total genomic DNA methylation with minimal toxicity. Further preclinical studies suggested that the interferon-signaling pathway is reactivated following decitabine exposure of cancer cells. We propose to build on our previous preclinical experiments to perform a phase I clinical trial to test whether a decitabine infusion can sensitize cancer cells to interferon-a in vivo.
In Specific Aim1 we plan to perform a phase I clinical trial to assess the toxicities of a continuous intravenous infusion of decitabine with escalating doses of subcutaneous PEG-IFN in patients with refractory metastatic cancer. The clinical protocol is designed to identify the dose limiting toxicity and the maximum tolerated dose of PEG-IFN in this combination.
In Specific Aim 2 we will perform molecular correlation studies to evaluate pretreatment and post treatment samples of blood, skin and tumor from patients to identify changes in global (genomic) DNA methylation, as well as evaluating promoter-specific methylation . Additional experiments will evaluate interferon signaling and DNA damage response pathways in normal and neoplastic cells. ? ? ?
| Al-Salihi, Mazin; Yu, Margaret; Burnett, David M et al. (2011) The depletion of DNA methyltransferase-1 and the epigenetic effects of 5-aza-2'deoxycytidine (decitabine) are differentially regulated by cell cycle progression. Epigenetics 6:1021-8 |
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