title: A phase I trial of depsipeptide (FR901228) in patients with advanced cancer.
abstract: Depsipeptide (FR901228) is a bicyclic peptide isolated from Chromobacterium violaceum that has demonstrated potent in vitro cytotoxic activity against human tumor cell lines and in vivo efficacy against human tumor xenografts. The primary mechanism of action is through inhibition of histone deacetylase. Initial development was halted due to significant cardiac toxicity. Subsequent studies performed at the National Cancer Institute demonstrated administration without cardiotoxicity was possible by varying the schedule of administration. A phase I trial was designed to determine the maximum tolerated dose and toxicity profile when administered as a 4-hour infusion weekly x 3 with one week rest. 33 Patients with advanced, incurable cancers were enrolled into this trial and treated with doses of Depsipeptide ranging from 1 mg/m2 to 17.7 mg/m2. At doses above 5 mg/m2, we observed common symptoms of nausea, vomiting, fatigue, and anorexia. Subtle changes in ECGs were seen in several patients. However, no cardiac enzyme abnormalities or reduction in ejection fraction were observed. The MTD was defined as 13.3 mg/m2 with dose limiting toxicities being grade 3 thrombocytopenia and fatigue. Depsipeptide can be safely administered when given as a 4-hour infusion and further clinical trials are warranted.
authors.affiliation: Georgetown University, 3800 Reservoir Rd, NW, Washington, DC, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
authors.forename: Naiyer
authors.initials: N
authors.lastname: Rizvi
authors.forename: John
authors.initials: J
authors.lastname: Kauh
authors.forename: William
authors.initials: W
authors.lastname: Dahut
authors.forename: Manuela
authors.initials: M
authors.lastname: Figuera
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Irving
authors.initials: I
authors.lastname: Wainer
authors.forename: Christoff
authors.initials: C
authors.lastname: Chaissang
authors.forename: Megan Zhaoyang
authors.initials: MZ
authors.lastname: Li
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hawkins
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047630:Depsipeptides; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013812:Therapeutics; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C087123:romidepsin