Preclinical Drug Response Metric Based on Cellular Response Phenotype Provides Better Pharmacogenomic Variables with Phenotype Relevance

Abstract

High-throughput screening of drug response in cultured cell lines is essential for studying therapeutic mechanisms and identifying molecular variants associated with sensitivity to drugs. Assessment of drug response is typically performed by constructing a dose-response curve of viability and summarizing it to a representative, such as IC50. However, this is limited by its dependency on the assay duration and lack of reflections regarding actual cellular response phenotypes. To address these limitations, we consider how each response-phenotype contributes to the overall growth behavior and propose an alternative method of drug response screening that takes into account the cellular response phenotype. In conventional drug response screening methods, the ranking of sensitivity depends on either the metric used to construct the dose-response curve or the representative factor used to summarize the curve. This ambiguity in conventional assessment methods is due to the fact that assessment methods are not consistent with the underlying principles of population dynamics. Instead, the suggested phenotype metrics provide all phenotypic rates of change that shape overall growth behavior at a given dose and better response classification, including the phenotypic mechanism of overall growth inhibition. This alternative high-throughput drug-response screening would improve preclinical pharmacogenomic analysis and the understanding of a therapeutic mechanism of action.

Duocarmycin SA Reduces Proliferation and Increases Apoptosis in Acute Myeloid Leukemia Cells In Vitro

“…Preclinical drug response studies using cultured cell lines are important for determining the therapeutic effectiveness of a drug. These types of studies allow for the characterization of the potency and the identification of the cellular effects of the test drug [27]. Furthermore, dose-response relationships are often used as a tool/metric to characterize the potency of a drug by providing the concentration of half the maximal inhibition (IC 50 ) of the drug [27].…”

“…These types of studies allow for the characterization of the potency and the identification of the cellular effects of the test drug [27]. Furthermore, dose-response relationships are often used as a tool/metric to characterize the potency of a drug by providing the concentration of half the maximal inhibition (IC 50 ) of the drug [27]. Therefore, to investigate whether DSA shows efficacy against AML cells, we cultured both AML cell lines with vehicle (DMSO) or seven increasing concentrations of DSA (1-1000 pM) for 72 h and analyzed the cell viability using the MTT assay (living cells undergoing respiration convert MTT to a purple formazan dye whose concentration is measured using a spectrophotometer).…”