Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


osu1249622434.pdf (1.31 MB)

ETD Abstract Container

Abstract Header

Mechanism-Based Computational Models to Study Pharmacological Actions of Anticancer Drugs

Yang, Jianning
http://rave.ohiolink.edu/etdc/view?acc_num=osu1249622434

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Pharmacy.
Chemotherapeutical agents with various mechanisms are generally used in combinations to achieve better efficacy, overcome resistance, and reduce side effects. Although combination chemotherapy showed success in some cases, the selection of anticancer agents for combination therapy and their dosing scheme remain to be further evaluated and optimized. In this dissertation, mechanism-based computational models were developed to study pharmacological actions of single anticancer drugs as well as their combinations. The models were based on the cell cycle kinetics of cancer cells and predicted multiple endpoints that are important to treatment outcome, such as apoptosis, senescence, clonogenicity and polyploid. These models have the potential to be applied in the optimization of chemotherapy regimen, either for monotherapy or combination therapy. In Chapter 2, the antagonistic effect of high dose suramin on paclitaxel was evaluated. A pharmacodynamic model was established to describe suramin-induced cell cycle arrest. This model was integrated with the pharmacodynamic model of paclitaxel to simulate effects after combination treatments. The integrated model predicted antagonism, indicating that the partial cell-cycle block induced by suramin can explain the observed antagonism on paclitaxel effect at elevated suramin concentrations. Chapter 3 established a pharmacodynamic model of the DNA-damaging agent cisplatin. The model successfully predicted in vitro cisplatin effects. A pharmacodynamic model of suramin was developed in Chapter 4 and integrated with the pharmacodynamic model of cisplatin. The model described suramin alone effects as well as effects after combination treatments of suramin and cisplatin. The model was able to predict the biphasic effects of suramin in cisplatin-treated cancer cells. Chapter 5 linked the pharmacodynamic model of cisplatin with a pharmacokinetic model of cisplatin in mice, which was developed based on literature reported data. The integrated PK/PD model was used to evaluate different doses and treatment schedules of cisplatin. The simulated results indicated that compared to the standard regimen (defined as 10 mg/kg given on day 1 per cycle for a 3-week cycle), regimens with split dose increased tumor growth, while regimen with increased dose density slightly enhanced the effectiveness of treatment. This data suggests that treatment outcome is at least partly determined by treatment schedules.
Jessie Au (Advisor)
Guillaume Wientjes (Advisor)
Dennis McKay (Committee Member)
Matthew Allen (Committee Member)
177 p.
Oncology; Pharmaceuticals
mechanism-based; computational model; chemotherapy, combination therapy

Recommended Citations

Citations

  • Yang, J. (2009). Mechanism-Based Computational Models to Study Pharmacological Actions of Anticancer Drugs [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249622434

    APA Style (7th edition)

  • Yang, Jianning. Mechanism-Based Computational Models to Study Pharmacological Actions of Anticancer Drugs. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1249622434.

    MLA Style (8th edition)

  • Yang, Jianning. "Mechanism-Based Computational Models to Study Pharmacological Actions of Anticancer Drugs." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1249622434

    Chicago Manual of Style (17th edition)

osu1249622434
694
© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.