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Updated: May 3, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia
Katja Karjalainen1, Renata Pasqualini, Jorge E Cortes
1David H. Koch Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Biological and Environmental Sciences, Division of Biochemistry, The University of Helsinki, Helsinki, Finland.
Background:
The authors developed an ex vivo methodology to perform drug library screening against human leukemia.
Methods:
The strategy for this screening relied on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. Several advantages were observed: 1) partial recapitulation of the leukemia microenvironment, 2) use of native hemoglobin oxygenation as a real-time sensor/reporter, 3) cost-effectiveness, 4) species specificity, and 5) a format that enables high-throughput screening.
Results:
For a proof of concept, a chemical library (size, approximately 20,000 compounds) was screened against human leukemia cells. Seventy compounds were identified ("hit" rate, 0.35%; Z-factor = 0.71) that had activity, and 20 compounds were examined to identify 18 true-positive compounds (90%). Finally, the results demonstrated that carbonohydraxonic diamide group-containing compounds are potent antileukemia agents that induce cell death in leukemia cells and in patient-derived samples.
Conclusions:
The current results indicated that this unique functional assay can identify novel drug candidates and can help with the development of future applications in personalized drug selection for patients with leukemia.
