Phase II study of the histone deacetylase inhibitor MGCD 0103 in patients with previously treated chronic lymphocytic leukaemia
Historically, loss of tumour suppressor genes and genomic silencing via DNA mutation or deletion have been thought to contribute to tumorigenesis by permitting apoptotic escape, sustained growth, limitless replication, immunological evasion, and metastasis of the malignant cell. However, epigenetic modifications that favour transcriptionally repressive chromatin are also common in neoplastic transformation, particularly in B-cell malignancies (Koduru et al, 1995; Baur et al, 1999; Costello et al, 2000). CpG island promoter methylation and post-translational modifications of histone proteins alter chromatin conformation, favouring transcriptional repression and genomic silencing. Eukaryotic DNA is condensed 10 000fold via the nucleosome, a histone octamer consisting of a histone H3 and H4 tetramer and two histone H2A and H2B dimers. Post-translational modifications of histone proteins including histone acetylation are critical to transcriptional regulation of genes. Histone acetylation and histone deacyetylation regulated by histone acetyltransferases and histone deacetylases (HDACs) leads to either transcriptionally active hyperacetylated chromatin or transcriptionally repressive hypoacetylated chromatin, respectively. Four classes of HDACs remove acetyl groups from lysine residues in the N-terminal tails of core histones in protein repressor and chromatin remodelling complexes including HDACs 1, 2, 3 and 8 (class I isotypes located within the nucleus); HDACs 4, 5, 6, 7, 9 and 10 (class II isotypes which shuttle between the cytoplasm and the nucleus), Sirt 1–7 (class III istoypes), and HDAC 11 (class IV isotype) (de Ruijter et al, 2003). While genomic deletions and mutations irreversibly alter the sequence of a gene, histone modifications can be readily targeted by therapies that inhibit histone deacetylation. In addition to nuclear modification of histone proteins, several of the class II HDAC enzymes can also Kristie A. Blum, Anjani Advani, Louis Fernandez, Richard Van Der Jagt, Joseph Brandwein, Suman Kambhampati, Jeannine Kassis, Melanie Davis, Claire Bonfils, Marja Dubay, Julie Dumouchel, Michel Drouin, David M. Lucas, Robert E. Martell and John C. Byrd The Ohio State University Medical Center, Columbus, OH, The Cleveland Clinic Foundation, Cleveland, OH, USA, Queen Elizabeth II Health Sciences Center, Halifax, NS, Ottawa Hospital-General Campus, Ottawa, ON, Princess Margaret Hospital, Toronto, ON, Canada, Veteran Affairs Medical Center, Kansas City, MO, USA, University of Montreal, QC, and MethylGene Inc., Montreal, QC, Canada