The activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) were evaluated in patients with refractory cutaneous T-cell lymphoma (CTCL). Group 1 received vorinostat 400 mg daily, group 2 received vorinostat 300 mg twice daily for 3 days with 4 days rest, and group 3 received vorinostat 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice daily. Treatment continued until disease progression or intolerable toxicity. The primary objective was to deter-

Recent discoveries suggesting essential bioactivities of nitric oxide (NO') in the lung are difficult to reconcile with the established pulmbnary cytotoxicity of this common air pollutant. These conflicting observations suggest that metabolic intermediaries may exist in the lung to modulate the bioactivity and toxicity of NO'. We report that S-nitrosothiols (RS-NO), predominantly the adduct with glutathione, are present at nano-to micromolar concentrations in the airways of normal subjects and that their levels vary in different human pathophysiologic states. These endogenous RS-NO are longlived, potent relaxants of human airways under physiological 02 concentrations. Moreover, RS-NO form in high concentrations upon administration of NO gas. Nitrite (10-20 ,M) is found in airway lining fluid in concentrations linearly proportional to leukocyte counts, suggestive of local NO' metabolism. NO itself was not detected either free in solution or in complexes with transition metals. These observations may provide insight into the means by which NO is packaged in biological systems to preserve its bioactivity and limit its potential 02-dependent toicity and suggest an important role for NO' in regulation of airway luminal homeostasis.There is accumulating evidence that nitric oxide (NO') is produced in mammalian airways: constitutive and inducible forms of NO synthase have recently been identified in the lung (1, 2), oxides of nitrogen (NOx) are produced by airway cells (3), and exhaled NO gas can be measured in nonsmoking volunteers (4). Potential sources of NO' include the lung parenchyma itself [smooth muscle, mast cells, nerves, and epithelium (1-3, 5-8)] as well as the cellular constituents of airway lining fluid [macrophages and neutrophils (1, 2, 9-11)]. NO has well established vasodilator properties that may play a role in the physiological regulation of blood flow and pressure in the pulmonary circulation (12). Although more disputed (13), the smooth muscle relaxant effects of NO' in airways suggest that it may have an additional role as a bronchodilator (14)(15)(16).NO', a common air pollutant and component of cigarette smoke, has been viewed as highly toxic to the lung, in part as a consequence of the high ambient 02 tension (17)(18)(19)(20)(21)(22). The reactions of NO with ambient 02 and superoxide (02 ) yield more reactive NO,, including nitrogen dioxide (NO) and peroxynitrite (OONO-), which are implicated in bronchiolitis and lung edema (17,20,21,23,24). There is additional concern that the oxidative metabolism of NO may lead to formation of carcinogenic nitrosoamines (25,26). Notably, these oxidative reactions of NO also result in the rapid loss of its smooth muscle relaxant activity (27, 28).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.An alternative metabolic pathway for NOI of potential biological relevance involves the reaction wit...

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug-related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic im-

Although growth factor receptors are generally thought to carry out their role in signal transduction at the cell surface, many of these transmembrane proteins translocate to the nucleus after ligand stimulation. Here, we show that the nuclear translocation of fibroblast growth factor receptor (FGFR)1 occurs via a mechanism distinct from classical nuclear import but dependent on importin β, a component of multiple nuclear import pathways. Furthermore, we show that nuclear FGFR1 induces c-Jun and is involved in the regulation of cell proliferation. These data are the first description of a nuclear import pathway for transmembrane growth factor receptors and elucidate a novel signal transduction pathway from the cell surface to the nucleus.

A B S T R A C T PurposeVorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM). Patients and MethodsPatients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period. ResultsA total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28ϩ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P ϭ .02). ConclusionVorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.