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Pharmacodynamic Monitoring of Molecular-Targeted Agents in the Peripheral Blood of Leukemia Patients Using Flow Cytometry
1 Division of Applied Molecular Oncology, Ontario Cancer Institute, University of Toronto, Ontario, Canada Correspondence: Address correspondence to: David W. Hedley, MD, Department of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Ave., Toronto, Ontario, M5G 2M9, Canada; e-mail: david.hedley{at}uhn.on.ca. 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.
Key Words: Signal transduction • phosphospecific antibody • mTOR; ERK • stem cell factor • flow cytometry • leukemia Abbreviations: AML, acute myeloid leukemia • CML, chronic myeloid leukemia • EGFR, epidermal growth factor receptor • ERK, extracellular-regulated kinase • MEK, MAP and ERK kinase • mTOR, mammalian target of rapamycin • PMA, phorbol myristate acetate • SCF, stem cell factor • STAT, signal transducer and activator of transcription
Toxicologic Pathology, Vol. 36, No. 1,
133-139 (2008) |
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