Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer

Bibliographic Details
Main Author:	Alyamani, Mohammad
Language:	English
Published:	Cleveland State University / OhioLINK 2017
Subjects:	Analytical Chemistry Biomedical Research
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=csu1489752658080541

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-csu14897526580805412021-08-03T07:00:57Z Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer Alyamani, Mohammad Analytical Chemistry Biomedical Research Despite an array of improved treatment options over the past decade, prostate cancer remains the second leading cause of cancer mortality for men in the United States. Abiraterone and galeterone are oral steroidal compounds that are used to treat metastatic castration-resistant prostate cancer (CRPC). Abiraterone blocks 17a-hydroxylase/17,20-lyase (CYP17A1), an enzyme required for androgen synthesis. Galeterone inhibits CYP17A1, blocks the androgen receptor (AR), and decreases AR protein levels. Both drugs share the same structure with endogenous androgens such as dehydroepiandrosterone, which are substrates for the enzyme, 3ß-hydroxysteroid dehydrogenase (3ßHSD). Metabolites of 3ßHSD undergo further metabolism to produce the AR ligand, testosterone and dihydrotestosterone.Overall this project aimed to investigate the steroidogenic metabolism of abiraterone and galeterone and evaluate the metabolites’ role in prostate cancer. The background on prostate cancer, steroid biosynthesis, and treatment options is described in Chapter I. Chapter II describes the development and validation of a liquid chromatography mass spectrometry method LC-MS/MS to determine abiraterone metabolites. My method distinguished between all the diastereoisomers with conventional chromatographic conditions. In chapter III and IV my validated LC-MS/MS method was utilized to study the metabolism of abiraterone in vitro using prostate cancer cell lines and in vivo using mice. It also helped in determining abiraterone metabolites in a pharmacokinetic trial in healthy human subjects and in prostate cancer patients enrolled in several clinical trials. The trials aimed to evaluate the standard dose of abiraterone acetate, combining abiraterone acetate with androgen deprivation therapy (ADT), adding dutasteride (an SRD5A inhibitor), or increasing the frequency of the standard dose of abiraterone acetate. In chapter V, galeterone metabolism was studied in vitro and in vivo and the metabolites’ activities were evaluated for their roles in prostate cancer. Chapter VI discusses the overall conclusions and future directions.This project identified a new subset of abiraterone and galeterone metabolites that are generated by steroidogenic enzyme conversion. These metabolites had opposing effects on prostate cancer. These findings suggest a common pathway for steroidal drugs with a Δ5, 3ß-hydroxyl structure. This project also provides new strategies in prostate cancer treatment that will make the current treatment options more beneficial. 2017-03-22 English text Cleveland State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=csu1489752658080541 http://rave.ohiolink.edu/etdc/view?acc_num=csu1489752658080541 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Analytical Chemistry Biomedical Research
spellingShingle	Analytical Chemistry Biomedical Research Alyamani, Mohammad Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer
author	Alyamani, Mohammad
author_facet	Alyamani, Mohammad
author_sort	Alyamani, Mohammad
title	Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer
title_short	Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer
title_full	Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer
title_fullStr	Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer
title_full_unstemmed	Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer
title_sort	determination of novel metabolites of therapeutic agents used in the treatment of castration-resistant prostate cancer
publisher	Cleveland State University / OhioLINK
publishDate	2017
url	http://rave.ohiolink.edu/etdc/view?acc_num=csu1489752658080541
work_keys_str_mv	AT alyamanimohammad determinationofnovelmetabolitesoftherapeuticagentsusedinthetreatmentofcastrationresistantprostatecancer
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Determination of Novel Metabolites of Therapeutic Agents used in the Treatment of Castration-Resistant Prostate Cancer

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