Pharmacodynamic Monitoring of Molecular-Targeted Agents in the Peripheral Blood of Leukemia Patients Using Flow Cytometry

David W. Hedley, Sue Chow, Charles Goolsby, T. Vincent Shankey

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

The introduction of specific, molecular-targeted drugs is radically changing cancer treatment. Pharmacodynamics, which measures drug effects on the host, is key during early-phase clinical trials of novel agents to determine the relations between drug dose and target inhibition as well as measure the downstream effects of target inhibition on the cancer. In this article, we describe the application of flow cytometry to the pharmacodynamic monitoring of molecular-targeted agents in leukemia patients. The methods are based on current clinical flow-cytometry applications, with the addition of phosphospecific antibodies to measure the activation states of intracellular signaling elements and the introduction of techniques that maintain drug–target equilibrium during sample preparation. Using this approach, we successfully showed dose-dependent inhibition of c-Kit during a phase I clinical trial treating acute leukemia patients with the novel agent sorafenib. Further refinements identify considerable interpatient variation in signaling activity within leukemic blast populations, suggesting that an individualized approach to treatment based on flow cytometric monitoring might be advantageous. Improvements in sample turnaround offer the potential to introduce real-time pharmacodynamic monitoring during early-phase clinical trials.

Original languageEnglish (US)
Pages (from-to)133-139
Number of pages7
JournalToxicologic Pathology
Volume36
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Signal transduction
  • flow cytometry
  • leukemia
  • mTOR; ERK
  • phosphospecific antibody
  • stem cell factor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Toxicology
  • Cell Biology

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