type dependent and context dependent. Several recent reviews have addressed this issue and have detailed each possible mechanism . One assumption is that cell death is caused by Procollagen C Proteinase the re expression of repressed genes upon HDACI treatment; however, HDACIs have the ability to induce cell death by other mechanisms independent of re expression of genes. It has also been noted that combination of epigenetic inhibitors results in synergistic cell death and it is yet unclear if this synergism reflects the re expression of silenced genes or potentiation of cell death through acetylation of non histone proteins .
HDACI mediated cell lethality can be generalized into several different mechanisms: acetylation and disruption of the activity of client proteins for the heat shock proteins; perturbation of the NFkB pathway; up regulation Imatinib and activation of the extrinsic apoptotic pathway ; induction of oxidative injury ; generation of pro apoptotic second messengers such as ceramide. Again the data clearly suggests that the mechanism actually causing cancer cell death is very cell type specific. Understanding which of these mechanisms is operative in a specific cancer type and which HDAC are responsible may be critical to optimizing their rational incorporation into combination regimens HDACIs currently in clinical development cover pan HDACIs and somewhat isotype selective agents . With the approval of Zolinza by the FDA for the treatment of CTCL and with other histone deacetylase inhibitors awaiting approval for various cancers, this will hopefully prompt the investigation of histone deacetylase inhibitors into a broader range of disease states where altered chromatin function may play a role in their pathophysiology .
2.1. Vorinostat : clinical update The sensitivity of CTCL cells to dermatology vorinostat was demonstrated in cell lines and in primary peripheral blood lymphocytes from CTCL patients . In normal PBLs vorinostat increased apoptosis from 6 to 13% whereas in CTCL patient PBLs vorinostat increased apoptosis from 15 to 32%, suggesting selectivity of vorinostat for malignant versus normal cells. Vorinostat increased the acetylation of histones H2B, H3 and H4 and also increased the expression of p21 and Bax while decreasing the expression of STAT6 and decreasing levels of phospho STAT6; all ultimately leading to the activation of caspase 3, cleavage of PARP and apoptosis .
Similar results have been seen for romidepsin in Hut78 cells . Generally, vorinostat has been well tolerated in Phase I studies administered either i.v. or orally. The dose limiting toxicities observed in these studies included gastrointestinal , anorexia, dehydration, fatigue and myelosuppression neutropenia and/or leukopenia) . HDAC inhibition was demonstrated in patients as increased accumulation of acetylated histones in tumors, bone marrow and peripheral blood cells. Phase I studies with vorinostat have resulted in complete and partial responses in both refractory solid and hematological malignancies. The major adverse events observed with vorinostat differ by route of administration, i.v. or oral, possibly due to differences in pharmacokinetics; oral vorinostat produced fatigue, diarrhea, anorexia and dehydration as major AEs.