Multiscale Model Identifies Improved Schedule for Treatment of Acute Myeloid Leukemia In Vitro With the Mcl‐1 Inhibitor AZD5991
| Autor: | Francis D. Gibbons, Haley Woods, Matthew A. Belmonte, Ardeshir Goliaei, Douglas Ferguson, Adriana E. Tron, Bree B. Aldridge, J. Paul Secrist, Adrian J. Fretland, Lisa Drew |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Myeloid
Macrocyclic Compounds Cell Antineoplastic Agents Apoptosis Article Drug Administration Schedule Mice Cell Line Tumor hemic and lymphatic diseases Medicine Animals Humans Pharmacology (medical) business.industry Research lcsh:RM1-950 Myeloid leukemia Articles Cell cycle medicine.disease Xenograft Model Antitumor Assays In vitro Lymphoma Leukemia Leukemia Myeloid Acute medicine.anatomical_structure lcsh:Therapeutics. Pharmacology Cell culture Drug Resistance Neoplasm Modeling and Simulation Models Animal Cancer research Myeloid Cell Leukemia Sequence 1 Protein business |
| Zdroj: | CPT: Pharmacometrics & Systems Pharmacology, Vol 9, Iss 10, Pp 561-570 (2020) CPT: Pharmacometrics & Systems Pharmacology |
| ISSN: | 2163-8306 |
| Popis: | Anticancer efficacy is driven not only by dose but also by frequency and duration of treatment. We describe a multiscale model combining cell cycle, cellular heterogeneity of B-cell lymphoma 2 family proteins, and pharmacology of AZD5991, a potent small-molecule inhibitor of myeloid cell leukemia 1 (Mcl-1). The model was calibrated using in vitro viability data for the MV-4-11 acute myeloid leukemia cell line under continuous incubation for 72 hours at concentrations of 0.03-30 μM. Using a virtual screen, we identified two schedules as having significantly different predicted efficacy and showed experimentally that a "short" schedule (treating cells for 6 of 24 hours) is significantly better able to maintain the rate of cell kill during treatment than a "long" schedule (18 of 24 hours). This work suggests that resistance can be driven by heterogeneity in protein expression of Mcl-1 alone without requiring mutation or resistant subclones and demonstrates the utility of mathematical models in efficiently identifying regimens for experimental exploration. |
| Databáze: | OpenAIRE |
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