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Ye Feng Ph.D Dissertation Title.pdf (13.73 MB)

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DEVELOPMENT OF QUANTITATIVE BIOANALYTICAL METHODS FOR THE PHARMACOLOGICAL STUDIES OF ANTI-CANCER DRUGS

Feng, Ye
http://rave.ohiolink.edu/etdc/view?acc_num=csu1392249778

Abstract Details

, Doctor of Philosophy in Clinical-Bioanalytical Chemistry, Cleveland State University, College of Sciences and Health Professions.
In the anticancer drug discovery and therapy development, it is essential to understand the pharmacological properties of the drugs. Today, pharmaceutical analysis is employed throughout the whole drug discovery and development process. Pharmacokinetic-pharmacodynamic relationships are playing an increasingly important role in decisions on the rational development and use of new drugs; and they can provide a detailed knowledge of the mechanism of the drug and a better understanding of the molecular targets on which they act. Due to the significance of pharmacological analysis, sensitive analytical methods are critically needed for pharmacological studies. Therefore, our long-term goal is to provide guidelines in pharmacological studies of the anticancer drugs by quantitatively evaluating the molecular mechanisms of the drugs. In this dissertation, the theory behind the analytical processes and modern bioanalytical technologies, together with their applications in pharmacological studies are discussed in Chapter 1. Dependent on the type of molecules analyzed, different methods were developed to achieve the accurate and reliable detection. Specifically, the development of two HPLC methods with both the UV (Chapter 2) and MS (Chapter 3)detection for analysis of triapine, a ribonucleotide reductase inhibitor, is presented. In the UV method, the chelating nature of triapine was investigated by spectrophotometry, which provides an effective strategy to avoid the unwanted complexation reaction in the quantitation of triapine. An LC-MS/MS method was successfully applied to measurements of patients’ samples for pharmacokinetic studies of this drug. Another LC-MS/MS method was developed for quantification of fludarabine incorporated in DNA (Chapter 4). To the best of our knowledge, this is the first LC-MS/MS method developed for quantification of the amount of fludarabine incorporated. The significance of this study is that it provides an accurate method to study the fludarabine pharmacological effect. Moreover, the cytotoxicity mechanism of fludarabine was revisited by developing an LC-MS/MS method in conjunction with enzymatic digestion (Chapter 5). In this study, we found that the vast majority of fludarabine was incorporated in the internal position. The significance of this finding is that it allows physicians to develop better therapeutic strategies to use this drug for treatment of cancer. Finally, we applied the LC-MS/MS method developed in the study of Chapters 4 and 5 to elucidate the action of fludarabine on RNA metabolism (Chapter 6). In this study, we successfully determined the quantity of fludarabine incorporated into RNA. In addition, we were able to elucidate the primary incorporation position of fludarabine in RNA.
Yan Xu (Committee Chair)
Baochuan Guo (Committee Member)
Aimin Zhou (Committee Member)
Bin Su (Committee Member)
Joanne Belovich, M. (Committee Member)
Chemistry

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Citations

  • Feng, Y. (2013). DEVELOPMENT OF QUANTITATIVE BIOANALYTICAL METHODS FOR THE PHARMACOLOGICAL STUDIES OF ANTI-CANCER DRUGS [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1392249778

    APA Style (7th edition)

  • Feng, Ye. DEVELOPMENT OF QUANTITATIVE BIOANALYTICAL METHODS FOR THE PHARMACOLOGICAL STUDIES OF ANTI-CANCER DRUGS. 2013. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1392249778.

    MLA Style (8th edition)

  • Feng, Ye. "DEVELOPMENT OF QUANTITATIVE BIOANALYTICAL METHODS FOR THE PHARMACOLOGICAL STUDIES OF ANTI-CANCER DRUGS." Doctoral dissertation, Cleveland State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=csu1392249778

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Cleveland State University and OhioLINK.