Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.
dc.contributor.author | Jain, Harsh Vardhan | |
dc.contributor.author | Richardson, Alan | |
dc.contributor.author | Müller, A | |
dc.contributor.author | Byrne, Helen M | |
dc.date.accessioned | 2014-01-23T08:59:14Z | en |
dc.date.available | 2014-01-23T08:59:14Z | en |
dc.date.issued | 2014 | en |
dc.identifier.citation | Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas. 2014, 9 (1):e81582 PLoS ONE | en |
dc.identifier.issn | 1932-6203 | en |
dc.identifier.pmid | 24400068 | en |
dc.identifier.doi | 10.1371/journal.pone.0081582 | en |
dc.identifier.uri | http://hdl.handle.net/10033/311718 | en |
dc.description.abstract | Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to PloS one | en |
dc.title | Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas. | en |
dc.type | Article | en |
dc.identifier.journal | PloS one | en |
refterms.dateFOA | 2018-06-13T00:18:45Z | |
html.description.abstract | Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics. |