Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models

Cancer Chemother Pharmacol. 1998;42 Suppl:S54-9. doi: 10.1007/s002800051080.

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.

Publication types

  • Clinical Trial
  • Comparative Study

MeSH terms

  • Adult
  • Alkaloids / pharmacokinetics
  • Alkaloids / pharmacology*
  • Alkaloids / toxicity
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Blood Proteins / metabolism
  • Chromatography, High Pressure Liquid
  • Dogs
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Humans
  • Infusions, Intravenous
  • Mice
  • Mice, Nude
  • Protein Binding
  • Protein Kinase C / antagonists & inhibitors*
  • Rats
  • Staurosporine / analogs & derivatives
  • Transplantation, Heterologous / immunology

Substances

  • Alkaloids
  • Antineoplastic Agents
  • Blood Proteins
  • Enzyme Inhibitors
  • 7-hydroxystaurosporine
  • Protein Kinase C
  • Staurosporine