Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.
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 pat...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3882219?pdf=render |
| _version_ | 1818358977974501376 |
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| author | Harsh Vardhan Jain Alan Richardson Michael Meyer-Hermann Helen M Byrne |
| author_facet | Harsh Vardhan Jain Alan Richardson Michael Meyer-Hermann Helen M Byrne |
| author_sort | Harsh Vardhan Jain |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T20:37:35Z |
| format | Article |
| id | doaj.art-c30ab7e8ad79481b967f90dbeb181e4f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T20:37:35Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c30ab7e8ad79481b967f90dbeb181e4f2022-12-21T23:32:15ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0191e8158210.1371/journal.pone.0081582Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.Harsh Vardhan JainAlan RichardsonMichael Meyer-HermannHelen M ByrnePlatinum 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.http://europepmc.org/articles/PMC3882219?pdf=render |
| spellingShingle | Harsh Vardhan Jain Alan Richardson Michael Meyer-Hermann Helen M Byrne Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. PLoS ONE |
| title | Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. |
| title_full | Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. |
| title_fullStr | Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. |
| title_full_unstemmed | Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. |
| title_short | Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas. |
| title_sort | exploiting the synergy between carboplatin and abt 737 in the treatment of ovarian carcinomas |
| url | http://europepmc.org/articles/PMC3882219?pdf=render |
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