Exposure time versus cytotoxicity for anticancer agents.

Autor: Evans DM; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Fang J; Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA., Silvers T; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Delosh R; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Laudeman J; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Ogle C; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Reinhart R; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Selby M; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Bowles L; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Connelly J; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Harris E; Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA., Krushkal J; Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA., Rubinstein L; Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA., Doroshow JH; Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA., Teicher BA; Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA. Beverly.Teicher@nih.gov.; Molecular Pharmacology Branch, National Cancer Institute, RM 4-W602, MSC 9735, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. Beverly.Teicher@nih.gov.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2019 Aug; Vol. 84 (2), pp. 359-371. Date of Electronic Publication: 2019 May 17.
DOI: 10.1007/s00280-019-03863-w
Abstrakt: Purpose: Time is a critical factor in drug action. The duration of inhibition of the target or residence time of the drug molecule on the target often guides drug scheduling.
Methods: The effects of time on the concentration-dependent cytotoxicity of approved and investigational agents [300 compounds] were examined in the NCI60 cell line panel in 2D at 2, 3, 7 and in 3D 11 days.
Results: There was a moderate positive linear relationship between data from the 2-day NCI60 screen and the 3-, 7- and 11-day and a strong positive linear relationship between 3-, 7- and 11-day luminescence screen IC 50 s by Pearson correlation analysis. Cell growth inhibition by agents selective for a specific cell cycle phase plateaued when susceptible cells were growth inhibited or killed. As time increased the depth of cell growth inhibition increased without change in the IC 50 . DNA interactive agents had decreasing IC 50 s with increasing exposure time. Epigenetic agents required longer exposure times; several were only cytotoxic after 11 days' exposure. For HDAC inhibitors, time had little or no effect on concentration response. There were potency differences amongst the three BET bromodomain inhibitors tested, and an exposure duration effect. The PARP inhibitors, rucaparib, niraparib, and veliparib reached IC 50 s < 10 μM in some cell lines after 11 days.
Conclusions: The results suggest that variations in compound exposure time may reflect either mechanism of action or compound chemical half-life. The activity of slow-acting compounds may optimally be assessed in spheroid models that can be monitored over prolonged incubation times.
Databáze: MEDLINE
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