title: A phase I clinical trial of 12- O-tetradecanoylphorbol-13-acetate for patients with relapsed/refractory malignancies.
abstract: Phorbol esters activate protein kinase C and modulate a variety of downstream cell signaling pathways. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a phorbol ester that induces differentiation or apoptosis in a variety of cell lines at low concentrations. A phase I dose escalation trial of TPA was undertaken for patients with relapsed or refractory malignancies. The starting dose was 0.063 mg/m2 and most patients were treated with an intravenous infusion of TPA on days 1-5 and 8-12 followed by a 2-week rest period prior to retreatment. Thirty-five patients were treated. A biological assay was used to monitor levels of TPA-like activity in the blood after treatment. Serious adverse events included individual episodes of gross hematuria, a grand mal seizure, syncope, and hypotension. Many patients had transient fatigue, mild dyspnea, fever, rigors, and muscular aches shortly after the infusion. Dose-limiting toxicities included syncope and hypotension at a dose of 0.188 mg/m2. Only a single patient had evidence of tumor response. These studies establish 0.125 mg/m2 as the maximally tolerated dose when TPA is administered on this schedule.
authors.affiliation: The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, NJ 08901, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Schaar
authors.forename: Lauri
authors.initials: L
authors.lastname: Goodell
authors.forename: Joseph
authors.initials: J
authors.lastname: Aisner
authors.forename: Xiao Xing
authors.initials: XX
authors.lastname: Cui
authors.forename: Zheng Tao
authors.initials: ZT
authors.lastname: Han
authors.forename: Richard
authors.initials: R
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Martin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grospe
authors.forename: Liesel
authors.initials: L
authors.lastname: Dudek
authors.forename: Joan
authors.initials: J
authors.lastname: Riley
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Manago
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Allan
authors.initials: A
authors.lastname: Conney
authors.forename: Roger K
authors.initials: RK
authors.lastname: Strair
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D013755:Tetradecanoylphorbol Acetate