• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    Studies on the effects of inhibitors of androgen synthesis in model system for prostate cancer

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Find Full text
    Author
    Grigoryev, Dmitry Nicholas
    Advisor
    Brodie, Angela
    Date
    1999
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Our laboratory have designed and synthesized a number of cytochrome P450 17alpha-hydroxylase/C17,20-lyase (P450c17) inhibitors with the aim of inhibiting androgen synthesis and as potential agents to treat prostate cancer. VN/63-1, VN/85-1, VN/87-1, VN/107-1, VN/108-1, and VN/109-1 inhibitor were chosen for study. To select the most potent inhibitors, a new method for evaluating inhibitors of the P450c17 enzyme was designed. Bacteria expressing the P450c17 were used as a source of the enzyme. HPLC was replaced by a rapid radiometric assay, acetic acid releasing assay. This new analytical system will be a powerful tool to accelerate the process of new compound selection. Utilizing this system, I showed that VN/85-1, VN/87-1, and VN/108-1 are the most potent inhibitors of P450c17. The effects of the new inhibitors on androgen dependent LNCaP and androgen independent PC-3 prostatic carcinoma cells proliferation were studied. I have shown that VN/85-1, VN/87-1, and VN/108-1 are the most potent inhibitors of LNCaP cell growth in vitro . VN/85-1 also has weak inhibitory effects against androgen independent PC-3 cells. The effects of azolyl steroids on LNCaP androgen receptor (AR) were determined. VN/63-1, VN/85-1, and VN/87-1 were full antagonists of LNCaP AR. Although, VN/107-1 , VN/108-1, and VN/109-1 were partial agonists of LNCaP AR, all of the evaluated inhibitors were antiandrogens against the wild-type AR. The new inhibitors were also evaluated in vivo. The male SCID mice bearing LNCaP tumor xenografts were utilized for new compounds evaluation. I showed that VN/85-1 and VN/87-1 have potent antitumor effects in this in vivo model. The ability of pregnenolone to stimulate LNCaP cell proliferation was discovered and investigated. I showed that this pregnenolone stimulation is mediated through the mutated AR and can be inhibited by our novel compounds, especially by VN/63-1, VN/85-1, and VN/87-1. This findings suggests that pregnenolone has a significant role in stimulating prostate cancer and that our new compounds by inhibiting not only androgens but also pregnenolone action may be more effective for treating prostate cancer than currently available agents.
    Description
    University of Maryland, Baltimore. Pharmacology and Experimental Therapeutics. Ph.D. 1999
    Keyword
    Biology, Molecular
    Health Sciences, Pharmacology
    Health Sciences, Oncology
    Prostate--Cancer
    Androgen Antagonists
    Mice
    Pregnenolone--antagonists & inhibitors
    Steroid Synthesis Inhibitors
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1278
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.