Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid.
BACKGROUND
Histone deacetylase inhibitors are a novel class of therapeutic agents that inhibit deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression. Phase I trials of intravenous and oral formulations of one such agent, vorinostat (suberoylanilide hydroxamic acid [SAHA]), have shown that it is safe and tolerable, that it inhibits histone deacetylation in peripheral blood mononuclear cells, and that it has a broad range of antitumor activity.


METHODS
Thirteen patients with mesothelioma were included in a phase I trial of oral SAHA. All but one had previously been treated with chemotherapy.


RESULTS
Four patients completed > or = 6 cycles of therapy; 2 patients demonstrated a partial response. The toxicities in this cohort of patients were similar to those observed in the entire phase I trial: primarily fatigue, dehydration, nausea, and vomiting.


CONCLUSIONS
Given the dearth of treatment options for patients with advanced mesothelioma who have progressed after first-line chemotherapy, these results are encouraging. A placebo-controlled, randomized phase III study of oral SAHA is now open for patients with mesothelioma in whom treatment with pemetrexed has failed.
Krug
Lee M
LM
Thoracic Oncology Service , Memorial Sloan-Kettering Cancer Center and Joan and Sanford Weill Medical College of Cornell University, New York, NY 10021, USA. krugl@mskcc.org
Curley
Tracy
T
Schwartz
Lawrence
L
Richardson
Stacie
S
Marks
Paul
P
Chiao
Judy
J
Kelly
W Kevin
WK
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008297:Male; D008654:Mesothelioma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000077337:Vorinostat
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat