Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

2006 ◽  
Vol 58 (3) ◽  
pp. 621-681 ◽  
Author(s):  
Ting-Chao Chou
Keyword(s):  
Experimental Design ◽  
Drug Combination ◽  
Theoretical Basis ◽  
Combination Studies ◽  
Computerized Simulation ◽  
Synergism And Antagonism

scholarly journals Experimental design for multi-drug combination studies using signaling networks

Biometrics ◽  
2017 ◽  
Vol 74 (2) ◽  
pp. 538-547 ◽  
Author(s):  
Hengzhen Huang ◽  
Hong-Bin Fang ◽  
Ming T. Tan
Keyword(s):  
Experimental Design ◽  
Drug Combination ◽  
Signaling Networks ◽  
Combination Studies

Drug combination studies of PS-1 and quercetin against rhodesain of Trypanosoma brucei rhodesiense

2021 ◽  
pp. 1-5
Author(s):  
Carla Di Chio ◽  
Santo Previti ◽  
Fabiola De Luca ◽  
Alessandro Allegra ◽  
Maria Zappalà ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Drug Combination ◽  
Trypanosoma Brucei Rhodesiense ◽  
Combination Studies

Preclinical evaluation of the ETS inhibitor TK216 against relapsed and refractory childhood leukemia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10033-10033
Author(s):  
Ritul Sharma ◽  
Satbir Thakur ◽  
Mohit Jain ◽  
Chunfen Zhang ◽  
Anne-Marie Langevin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Line ◽  
Drug Combination ◽  
Childhood Leukemia ◽  
Sensitive Cell Line ◽  
Pediatric Leukemia ◽  
Drug Synergy ◽  
Molecular Abnormalities ◽  
Anti Cancer ◽  
Combination Studies

10033 Background: Although survival rates have improved in the recent past, relapse and refractory disease remain a significant cause of death in children with leukemia. This calls for an urgent need for the development of novel therapies that could effectively treat leukemias in children. The E26 transformation specific (ETS) family of transcription factors regulate various normal cellular functions but are abnormally expressed in various cancers, including leukemia. TK216 is an ETS inhibitor, that has shown pre-clinical activity and clinical efficacy in solid tumors. In this study, we explore the feasibility of using TK216 as a therapeutic agent for the treatment of high risk refractory pediatric leukemia. Methods: A panel of pediatric leukemia derived cell lines and primary blast cells representing a spectrum of molecular abnormalities seen in pediatric leukemia were treated in vitro with TK216 to determine cytotoxicity. Normal lymphocytes were used as controls and cell viability was determined 72 hours post-treatment by Alamar blue assay. The induction of tumor cell apoptosis and target modulation were detected by Western blotting. Alterations in the cell cycle were assessed by FACS analysis with PI staining. Drug combination studies were carried out with established anti-leukemic agents to identify synergy for greater therapeutic efficiency. Results: TK216 decreased cell viability in leukemia cells compared to normal lymphocyte controls in a dose-dependent manner with variations in sensitivity noted with inherent molecular abnormalities. The IC50 values observed ranged from 0.22 µM for the most sensitive cell line, MV4-11 to 0.95 µM for least sensitive cell line, SUP-B15. Apoptosis induction upon TK216 treatment was confirmed by PARP cleavage and caspase 3 activation. Cell cycle analysis demonstrated increased sub-G1 population of cells after TK216 treatment. A strong correlation between sub-G1 population and sensitivity of the cell line towards TK216 (47% in MV4-11 vs 3.72% in SUP-B15) was observed. Screening of a panel of 200 FDA approved anti-cancer agents in drug combination studies identified potential agents for drug synergy. Significant drug synergy was noted with TK216 in combination with the epigenetic modifier 5-azacytidine and the Bcl-2 inhibitor, Venetoclax. [Combination Index for Venetoclax and TK216, mean = 0.65 for MV4-11 and 0.33 for SUP-B15]. Conclusions: Data from our study demonstrate that the ETS inhibitor TK216 induces apoptosis and cell cycle arrest in pediatric leukemia cells at physiologically relevant concentrations. Our combination studies identified distinct anti-cancer agents that could be used for developing effective drug combination regimens with TK216. Overall, our findings provide essential preclinical data for the consideration of TK216 in early phase clinical trials for the treatment of selected high-risk and refractory childhood leukemia.

Sign in / Sign up

Export Citation Format

Share Document