ABSTRACT
Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation, and/or apoptosis. In vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate alpha-ketoamide inhibitors was investigated using isolated enzyme preparations and cellular assays. In vitro selectivity for the HDAC isozymes (HDAC1/2, 3, 4/3, and 6) was not observed for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In T24 and HCT116 cells these compounds caused the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the alpha-ketoamides did not cause the accumulation of acetylated alpha-tubulin. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase.
Subject(s)
Amides/pharmacology , Breast Neoplasms/enzymology , Fibrosarcoma/enzymology , Histone Deacetylase Inhibitors , Histone Deacetylases/metabolism , Hydroxamic Acids/pharmacology , Amides/chemistry , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Activation/drug effects , Enzyme Inhibitors , Fibrosarcoma/pathology , Histone Deacetylases/chemistry , Humans , Hydroxamic Acids/chemistryABSTRACT
This study was designed to evaluate the late changes of aorta-coronary bypass grafts in patients who have been selected at random. Angiography was performed at mean intervals of 12 months (range 1 to 24 months) and 107 months (range 72 to 132 months) after operation in 55 randomly selected patients who were operated upon between 1971 and 1973. A total of 101 grafts were visualized. In particular, the evolution of early graft changes was investigated. At the first angiogram, 83% of the grafts were patent, including 7% with important narrowing. Later, the patency rate decreased to 65%, and there was a 9% incidence of significant narrowing in the graft or distal anastomosis. The patency rate was low in grafts to the circumflex artery and high in those to the left anterior descending artery. Early and late graft function was influenced by the viability of the corresponding region of the myocardium. It was not possible to predict late occlusions by the morphologic appearance of the graft at the early angiogram, nor did a distal stenosis in the recipient artery contribute to graft failure. These findings may be related to the long interval between angiograms as the yearly occlusion rate rose with increasing intervals between the studies. At 9 years, 25% of the patients had all grafts patent and no progression in nonbypassed vessels.
