title: Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models.
abstract: UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2-0.3 microM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human alpha1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in "real time" with phase I studies.
authors.affiliation: DTP Clinical Trials Unit, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD, USA. sausville@dtpax2.ncifcrf.gov
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: R D
authors.initials: RD
authors.lastname: Lush
authors.forename: D
authors.initials: D
authors.lastname: Headlee
authors.forename: A C
authors.initials: AC
authors.lastname: Smith
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: S G
authors.initials: SG
authors.lastname: Arbuck
authors.forename: A M
authors.initials: AM
authors.lastname: Senderowicz
authors.forename: E
authors.initials: E
authors.lastname: Fuse
authors.forename: H
authors.initials: H
authors.lastname: Tanii
authors.forename: T
authors.initials: T
authors.lastname: Kuwabara
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
mesh_terms: D000328:Adult; D000470:Alkaloids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007262:Infusions, Intravenous; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D019311:Staurosporine / Q000031:analogs & derivatives; D014183:Transplantation, Heterologous / Q000276:immunology
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D001798:Blood Proteins; D004791:Enzyme Inhibitors; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine