Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
MetadataShow full item record
AbstractPlatinum 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.
CitationExploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas. 2014, 9 (1):e81582 PLoS ONE
The following license files are associated with this item:
- The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas.
- Authors: Jain HV, Meyer-Hermann M
- Issue date: 2011 Feb 1
- The Bcl-2/Bcl-XL family inhibitor ABT-737 sensitizes ovarian cancer cells to carboplatin.
- Authors: Witham J, Valenti MR, De-Haven-Brandon AK, Vidot S, Eccles SA, Kaye SB, Richardson A
- Issue date: 2007 Dec 1
- Antagonism of Bcl-XL is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells.
- Authors: Abed MN, Abdullah MI, Richardson A
- Issue date: 2016 Apr 14
- Combined inhibition of Notch signaling and Bcl-2/Bcl-xL results in synergistic antimyeloma effect.
- Authors: Li M, Chen F, Clifton N, Sullivan DM, Dalton WS, Gabrilovich DI, Nefedova Y
- Issue date: 2010 Dec
- ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms.
- Authors: Kuroda J, Kimura S, Andreeff M, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Murotani Y, Matsumoto Y, Tanaka H, Strasser A, Taniwaki M, Maekawa T
- Issue date: 2008 Jan