دورية أكاديمية
Quantifying cell cycle-dependent drug sensitivities in cancer using a high throughput synchronisation and screening approach.
| العنوان: | Quantifying cell cycle-dependent drug sensitivities in cancer using a high throughput synchronisation and screening approach. |
|---|---|
| المؤلفون: | Johnson, Timothy I, Minteer, Christopher J, Kottmann, Daniel, Dunlop, Charles R, Fernández, Sandra Bernaldo de Quirós, Carnevalli, Larissa S, Wallez, Yann, Lau, Alan, Richards, Frances M, Jodrell, Duncan I |
| بيانات النشر: | Elsevier BV //dx.doi.org/10.1016/j.ebiom.2021.103396 EBioMedicine |
| سنة النشر: | 2021 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Cancer, cell cycle, combination treatment, high throughput screening, synchronisation, Cell Culture Techniques, Cell Line, Tumor, Cell Proliferation, Cell Survival, Deoxycytidine, Drug Screening Assays, Antitumor, Drug Synergism, HeLa Cells, High-Throughput Screening Assays, Humans, MCF-7 Cells, Neoplasms, Nocodazole, Piperazines, Pyridines, Small Molecule Libraries, Time Factors, Tubulin Modulators, Gemcitabine |
| الوصف: | BACKGROUND: Chemotherapy and targeted agent anti-cancer efficacy is largely dependent on the proliferative state of tumours, as exemplified by agents that target DNA synthesis/replication or mitosis. As a result, cell cycle specificities of a number of cancer drugs are well known. However, they are yet to be described in a quantifiable manner. METHODS: A scalable cell synchronisation protocol used to screen a library of 235 anti-cancer compounds exposed over six hours in G1 or S/G2 accumulated AsPC-1 cells to generate a cell cycle specificity (CCS) score. FINDINGS: The synchronisation method was associated with reduced method-related cytotoxicity compared to nocodazole, delivering sufficient cell cycle purity and cell numbers to run high-throughput drug library screens. Compounds were identified with G1 and S/G2-associated specificities that, overall, functionally matched with a compound's target/mechanism of action. This annotation was used to describe a synergistic schedule using the CDK4/6 inhibitor, palbociclib, prior to gemcitabine/AZD6738 as well as describe the correlation between the CCS score and published synergistic/antagonistic drug schedules. INTERPRETATION: This is the first highly quantitative description of cell cycle-dependent drug sensitivities that utilised a tractable and tolerated method with potential uses outside the present study. Drug treatments such as those shown to be G1 or S/G2 associated may benefit from scheduling considerations such as after CDK4/6 inhibitors and being first in drug sequences respectively. FUNDING: Cancer Research UK (CRUK) Institute core grants C14303/A17197 and C9545/A29580. The Li Ka Shing Centre where this work was performed was generously funded by CK Hutchison Holdings Limited, the University of Cambridge, CRUK, The Atlantic Philanthropies and others. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/325399Test |
| DOI: | 10.17863/CAM.72855 |
| الإتاحة: | https://doi.org/10.17863/CAM.72855Test https://www.repository.cam.ac.uk/handle/1810/325399Test |
| حقوق: | Attribution-NonCommercial-NoDerivatives 4.0 International ; https://creativecommons.org/licenses/by-nc-nd/4.0Test/ |
| رقم الانضمام: | edsbas.3C7FA78F |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.72855 |
|---|