title: Pharmacodynamic monitoring of molecular-targeted agents in the peripheral blood of leukemia patients using flow cytometry.
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.
authors.affiliation: Division of Applied Molecular Oncology, Ontario Cancer Institute, University of Toronto, Ontario, Canada. david.hedley@uhn.on.ca
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
authors.forename: Sue
authors.initials: S
authors.lastname: Chow
authors.forename: Charles
authors.initials: C
authors.lastname: Goolsby
authors.forename: T Vincent
authors.initials: TV
authors.lastname: Shankey
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D016903:Drug Monitoring / Q000379:methods*; D005434:Flow Cytometry / Q000379:methods; D018390:Gene Targeting; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib