David M Evans1, Jianwen Fang2, Thomas Silvers1, Rene Delosh1, Julie Laudeman1, Chad Ogle1, Russell Reinhart1, Michael Selby1, Lori Bowles1, John Connelly1, Erik Harris1, Julia Krushkal2, Larry Rubinstein2, James H Doroshow3, Beverly A Teicher4,5. 1. Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. 2. Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA. 3. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA. 4. Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, 20852, USA. Beverly.Teicher@nih.gov. 5. Molecular Pharmacology Branch, National Cancer Institute, RM 4-W602, MSC 9735, 9609 Medical Center Drive, Bethesda, MD, 20892, USA. Beverly.Teicher@nih.gov.
Abstract
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 IC50s 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 IC50. DNA interactive agents had decreasing IC50s 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 IC50s < 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.
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 IC50s 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 IC50. DNA interactive agents had decreasing IC50s 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 IC50s < 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.
Entities:
Keywords:
Concentration times time; CxT; Epigenetic agents; NCI60
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