The molecular basis of synergism between carboplatin and ABT-737 therapy targeting 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
AbstractResistance to standard chemotherapy (carboplatin + paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x(L), whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x(L) that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bcl-x(L) for survival. Numerical simulations predict the existence of a threshold of Bcl-x(L) below which these cells are unable to recover. Furthermore, co- plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists.
CitationThe molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas. 2011, 71 (3):705-15 Cancer Res.
The following license files are associated with this item:
- 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
- Exploiting the synergy between carboplatin and ABT-737 in the treatment of ovarian carcinomas.
- Authors: Jain HV, Richardson A, Meyer-Hermann M, Byrne HM
- Issue date: 2014
- Platinum compounds sensitize ovarian carcinoma cells to ABT-737 by modulation of the Mcl-1/Noxa axis.
- Authors: Simonin K, N'Diaye M, Lheureux S, Loussouarn C, Dutoit S, Briand M, Giffard F, Brotin E, Blanc-Fournier C, Poulain L
- Issue date: 2013 Apr
- Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors.
- Authors: Whitecross KF, Alsop AE, Cluse LA, Wiegmans A, Banks KM, Coomans C, Peart MJ, Newbold A, Lindemann RK, Johnstone RW
- Issue date: 2009 Feb 26
- The Bcl-2 homology domain 3 mimetic ABT-737 targets the apoptotic machinery in acute lymphoblastic leukemia resulting in synergistic in vitro and in vivo interactions with established drugs.
- Authors: High LM, Szymanska B, Wilczynska-Kalak U, Barber N, O'Brien R, Khaw SL, Vikstrom IB, Roberts AW, Lock RB
- Issue date: 2010 Mar