Treatment of canine haemangiosarcoma with suberoylanilide hydroxamic acid, a histone deacetylase inhibitor

2004 ◽  
Vol 2 (4) ◽  
pp. 243-248 ◽  
Author(s):  
L. A. Cohen ◽  
B. Powers ◽  
S. Amin ◽  
D. Desai
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Hydroxamic Acid ◽  
Suberoylanilide Hydroxamic Acid ◽  
Deacetylase Inhibitor

scholarly journals Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer

2005 ◽  
Vol 23 (17) ◽  
pp. 3923-3931 ◽  
Author(s):  
William Kevin Kelly ◽  
Owen A. O'Connor ◽  
Lee M. Krug ◽  
Judy H. Chiao ◽  
Mark Heaney ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Advanced Cancer ◽  
Histone Deacetylase Inhibitor ◽  
Hydroxamic Acid ◽  
Pharmacokinetic Profile ◽  
Enzyme Linked Immunosorbent Assay ◽  
Suberoylanilide Hydroxamic Acid ◽  
Linear Pharmacokinetics ◽  
Deacetylase Inhibitor ◽  
Post Therapy

Purpose To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. Patients and Methods Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. Results Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. Conclusions Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.

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