Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity
Abstract In vitro cellular assays are indispensable tools for preclinical understanding of therapeutic candidates. Herein, we have outlined methods for robust determination of cellular sensitivities by adapting drug-induced growth-rate inhibition analysis combined with intracellular drug exposure me...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-86919-7 |
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| author | Dolonchampa Maji Malerie Wolke Shamim Khaja John P. Savaryn John C. Kalvass Gary J. Jenkins |
| author_facet | Dolonchampa Maji Malerie Wolke Shamim Khaja John P. Savaryn John C. Kalvass Gary J. Jenkins |
| author_sort | Dolonchampa Maji |
| collection | DOAJ |
| description | Abstract In vitro cellular assays are indispensable tools for preclinical understanding of therapeutic candidates. Herein, we have outlined methods for robust determination of cellular sensitivities by adapting drug-induced growth-rate inhibition analysis combined with intracellular drug exposure measurements. Using two auristatins as tool molecules, we demonstrate wide variety of cellular response in sensitive versus resistant cancer cells, as well as in a toxicity-relevant cell type. Cellular response analysis generates metrics describing efficacious extracellular concentrations of drug, as well as the phenotype of response–cytotoxic versus cytostatic. Cell associated drug measurements bridge the gap between extracellular drug concentrations and exposure at intracellular sites required for a desired pharmacodynamic response. Such methods can complement rational drug design by providing thorough understanding of the drug mechanism of action, guide mechanistic selection of target indication and inform exposure-response analysis at various stages of drug discovery. |
| format | Article |
| id | doaj-art-c80b29f3cb1e4db29f705298aa4f6470 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-c80b29f3cb1e4db29f705298aa4f64702025-08-20T02:43:15ZengNature PortfolioScientific Reports2045-23222025-02-0115111010.1038/s41598-025-86919-7Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivityDolonchampa Maji0Malerie Wolke1Shamim Khaja2John P. Savaryn3John C. Kalvass4Gary J. Jenkins5Quantitative, Translational & ADME Sciences, AbbVie, IncQuantitative, Translational & ADME Sciences, AbbVie, IncQuantitative, Translational & ADME Sciences, AbbVie, IncQuantitative, Translational & ADME Sciences, AbbVie, IncQuantitative, Translational & ADME Sciences, AbbVie, IncQuantitative, Translational & ADME Sciences, AbbVie, IncAbstract In vitro cellular assays are indispensable tools for preclinical understanding of therapeutic candidates. Herein, we have outlined methods for robust determination of cellular sensitivities by adapting drug-induced growth-rate inhibition analysis combined with intracellular drug exposure measurements. Using two auristatins as tool molecules, we demonstrate wide variety of cellular response in sensitive versus resistant cancer cells, as well as in a toxicity-relevant cell type. Cellular response analysis generates metrics describing efficacious extracellular concentrations of drug, as well as the phenotype of response–cytotoxic versus cytostatic. Cell associated drug measurements bridge the gap between extracellular drug concentrations and exposure at intracellular sites required for a desired pharmacodynamic response. Such methods can complement rational drug design by providing thorough understanding of the drug mechanism of action, guide mechanistic selection of target indication and inform exposure-response analysis at various stages of drug discovery.https://doi.org/10.1038/s41598-025-86919-7 |
| spellingShingle | Dolonchampa Maji Malerie Wolke Shamim Khaja John P. Savaryn John C. Kalvass Gary J. Jenkins Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity Scientific Reports |
| title | Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity |
| title_full | Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity |
| title_fullStr | Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity |
| title_full_unstemmed | Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity |
| title_short | Application of drug-induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity |
| title_sort | application of drug induced growth rate inhibition and intracellular drug exposures for comprehensive evaluation of cellular drug sensitivity |
| url | https://doi.org/10.1038/s41598-025-86919-7 |
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