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Approaches to prostate cancer imaging and therapy: the use of pharmacokinetics, metabolism and biodistribution to identify new drugs

Yang, Jun
http://rave.ohiolink.edu/etdc/view?acc_num=osu1133362520

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Pharmacy.
Prostate cancer is one of the most common cancers and remains the second leading cause of death from cancer in men. Metastatic prostate tumors express the androgen receptor (AR) regardless of their sensitivity to hormonal therapy. This offers a cellular target for receptor-mediated imaging or treatment of prostate cancer. We first identified a series of novel agents that can be used to image and treat advanced prostate cancer via high affinity interaction with the AR. One of the most promising compounds, S-26, demonstrated a favorable receptor specificity profile, pharmacokinetic properties, and nonsteroidal structure, making it amenable to further optimization for AR mediated imaging. In vivo biodistribution studies showed that radiolabeled S-26 does not accumulate in AR-rich tissues. In vivo metabolism studies were performed to further understand the factors governing disposition of this ligand. The extensive plasma clearance of S-26 and unstable iodine substituent in the A ring likely contributed to its lack of AR tissue selectivity in vivo. During studies to elaborate new pharmacophores for the human AR, we discovered a series of bis-indole analogs that do not bind the AR, but exhibit potent cytotoxic activity in a variety of human tumor cell lines. One lead compound, bis-indole I-13, inhibited the growth of a number of human cancer cell lines, including the high P-glycoprotein expressing cell line, with IC50 in the range of 0.034 to 0.162 µM. Studies of in vivo pharmacokinetics, toxicity, antitumor activity in PC-3 xenograft, and metabolism demonstrated that bis-indole analogs represent a novel class of anticancer drugs for prostate cancer and offer hope for achievable pharmacologic activity in the clinic.
James Dalton (Advisor)
Health Sciences, Pharmacy
Pharmacokinetics; metabolism; biodistribution

Recommended Citations

Citations

  • Yang, J. (2005). Approaches to prostate cancer imaging and therapy: the use of pharmacokinetics, metabolism and biodistribution to identify new drugs [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1133362520

    APA Style (7th edition)

  • Yang, Jun. Approaches to prostate cancer imaging and therapy: the use of pharmacokinetics, metabolism and biodistribution to identify new drugs. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1133362520.

    MLA Style (8th edition)

  • Yang, Jun. "Approaches to prostate cancer imaging and therapy: the use of pharmacokinetics, metabolism and biodistribution to identify new drugs." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1133362520

    Chicago Manual of Style (17th edition)

osu1133362520
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.