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Electrophilic androgen receptor ligands as chemotherapeutic agents for prostate cancer

Xu, Huiping
http://rave.ohiolink.edu/etdc/view?acc_num=osu1089126757

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Pharmacy.
It has been well established that androgen receptor plays important roles in growth of the prostate and prostate tumors. Androgen blockade is used as the primary therapy for advanced prostate cancers. The ultimate goal of this research project was to discover and develop novel chemotherapeutic agents for prostate cancer from a series of nonsteroidal androgen receptor ligands that were designed and synthesized in our laboratories. Androgen receptor affinity and cell growth inhibition of these novel compounds varied dramatically. There was no general relationship between androgen receptor binding affinity and cell growth inhibitory effects of these ligands with only few exceptions. There were a number of compounds that displayed selective growth inhibitory effects in cancer cell lines. Involvement of androgen receptor is not likely the major mechanism responsible for anticancer activity of the majority of active compounds. Five compounds with LNCaP selective cell growth inhibitory effects demonstrated irreversible binding to the androgen receptor, suggesting possible involvement of the androgen receptor in their action. After characterizing the nature of the interaction between lead candidates and the androgen receptor, one compound (H-3) with reversible androgen receptor binding and selective in vitro anticancer activity was selected for in vivo pharmacodynamic study in PC-3 tumor-bearing mice. H-3 inhibited the growth of PC-3 tumor xenografts in BALB/c nude mice at dose independent manner when the same dosing interval was employed. Greater efficacy was achieved with greater dosing intensity. However, H-3 was unable to cause shrinkage of PC-3 tumor xenografts. These observations can be explained by the fact that H-3 is a cytostatic rather than cytotoxic agent. Thus, H-3 is unlikely to be useful for prostate cancer therapy given that it is not a strong cell death inducer. In conclusion, a number of nonsteroidal compounds with selective anticancer activity were identified, and multimechanisms may be involved in their activity. The lead candidate used for in vivo pharmacodynamic study did not show strong anticancer activity in PC-3 tumor xenografts because it was not a cytotoxic but a cytostatic agent.
James Dalton (Advisor)
290 p.
androgen receptor; prostate cancer; electrophilic androgen receptor ligands; cytotoxic; cytostatic; cell growth inhibition; androgens; antiandrogens; chemotherapeutic agents

Recommended Citations

Citations

  • Xu, H. (2004). Electrophilic androgen receptor ligands as chemotherapeutic agents for prostate cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1089126757

    APA Style (7th edition)

  • Xu, Huiping. Electrophilic androgen receptor ligands as chemotherapeutic agents for prostate cancer. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1089126757.

    MLA Style (8th edition)

  • Xu, Huiping. "Electrophilic androgen receptor ligands as chemotherapeutic agents for prostate cancer." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1089126757

    Chicago Manual of Style (17th edition)

osu1089126757
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© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.