Date of Award

2011

Degree Type

Dissertation

Department

Chemistry

First Advisor

Xu, Yan

Subject Headings

Antineoplastic agents, Pharmacology, Analytical chemistry, Pharmacy -- Research, Cancer -- Chemotherapy, Drug development -- Methodology, Liquid chromatography, Mass spectrometry

Abstract

In the development of anti-cancer drugs, it is essential to study the pharmacological profiles of the drugs. Among the analytical tools utilized in the pharmacological studies, LC-MS/MS has gained increased popularity due to its unequivocal sensitivity and specificity, as well as the ability of handling a wide variety of compounds with relatively simple sample preparation procedures. In this work, a brief review on the method rational, instrumentations, analytical method validation, and work flow of the method development was included. The processes of LC-MS/MS method development for the pharmacological studies of three anti-cancer drugs (i.e., methoxyamine, fludarabine, and 6-benzylthioinosine) were illustrated. To be more specific, a tetra-enzyme cocktail utilized for DNA adducts release was introduced. LC-MS/MS methods for the analysis of methoxyamine modified DNA abasic sites and fludarabine incorporated in DNA were developed toward the DNA adducts released from DNA with the enzyme cocktail. The methods were applied to the drug effect and drug mechanism studies. Another two LC-MS/MS method was developed for the quantification of 2-fluoroadenine released from the fludarabine incorporated DNA and free 6-benzylthioinosine drug molecule in mouse and human plasma. The first method helped to provide direct evidence to a newly proposed drug resistance mechanism toward fludarabine through DNA base excision repair while the second method realized the pharmacokinetic studies of the drug. The results in this work not only demonstrated the capability of LC-MS/MS in solving sophisticated pharmacological puzzles, but will provide useful information guiding the preclinical studies and clinical therapy development of the anti-cancer drugs listed above

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