Demethylating Agents

Caspase-8 expression acts as a key determinant of sensitivity for apoptosis induced by death-inducing lig-ands or cytotoxic drugs. Caspase 8 has been shown to be preferentially silenced in neuroblastoma (Teitz et al. 2000). In tumor cell lines resistant to TRAIL, anti-CD95 or TNF-alpha, caspase-8 protein and mRNA expression was decreased or absent without caspase-8 gene loss. Methylation-specific PCR revealed hypermethylation of caspase-8 regulatory sequences in cells with impaired caspase-8 expression. Treatment with the demethylation agent 5-Aza-2'-deoxycytidine (decita-bine) reversed hypermethylation of caspase-8 resulting in restoration of caspase-8 expression and recruitment and activation of caspase-8 for drug-induced apoptosis (Fulda et al. 2001; Eggert et al. 2001). The use of a demethylating agent in combination with chemotherapy is being tested in a phase-I trial in the COG.

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