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Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer

Sargeant, Aaron Matthew
http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876

Abstract Details

2009, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Prostate cancer is the most commonly diagnosed noncutaneous cancer and the second leading cause of cancer death in men. To combat the assortment of genomic and cellular aberrations that occur with the progression of this disease, we have developed novel classes of histone deacetylase (HDAC) inhibitors, 3-phosphoinositide dependent protein kinase-1 (PDK1)/Akt inhibitors, and indole-3-carbinol analogs using phenylbutyrate, celecoxib, and indole-3-carbinol, respectively, as scaffolds. Here, we assess both the efficacy and safety of the lead compounds of these classes (OSU-HDAC42, OSU-03012, and OSU-A9) administered orally in a series of preclinical studies carried out, in part, in preparation for prevention and regression trials in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Following the acquisition of relevant in vitro and dose-ranging data, the tumor-suppressive efficacy of selected doses was evaluated in PC-3 xenograft ± TRAMP-C2 syngeneic mouse models. The oral drug formulation found to achieve the most promising benefit-risk ratio was incorporated into a diet and administered to TRAMP mice for the assessment of its morphologic and molecular effects on the development of prostatic intraepithelial neoplasia (PIN) and carcinoma. Toxicity was evaluated by histopathologic, hematologic, and body and organ weight analysis. OSU-HDAC42 achieved the most potent blockade of prostate tumorigenesis reported in the TRAMP model, suppressing the absolute and relative weights of the urogenital tracts by 86% and 85%, respectively, in association with intraprostatic modulation of biomarkers indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. This compound, while sparing body weight, caused reversible testicular degeneration and hematologic alterations. In addition to its prostate chemopreventive effects, OSU-03012 was found to induce the hepatic biotransformation enzymatic system and caused phenotypic changes partially linked to sustained PDK1/Akt inhibition through inactivation of the downstream regulator of glycogen synthesis, glycogen synthase. OSU-A9 was compared vis-à-vis two slightly modified agents, of which the methylated derivative OSU-A9M was selected for continued lead optimization. Collectively, this work suggests therapeutic value in incorporating these novel compounds into the treatment regimen of patients with PIN, and reveals other biological parameters that should be considered for monitoring in the future preclinical and clinical use of these and similarly-targeted agents.
Ching-Shih Chen, PhD (Advisor)
Robert Brueggemeier, PhD (Committee Member)
Steven Clinton, MD, PhD (Committee Member)
Thomas Rosol, DVM, PhD (Committee Member)
181 p.
Animals; Biochemistry; Health Care; Molecules; Oncology; Pathology; Pharmaceuticals; Pharmacology; Therapy; Toxicology; Veterinary Services
prostate cancer; chemoprevention; anticancer therapy; mouse models; small molecules; veterinary pathology; toxicologic pathology; TRAMP; xenograft; risk assessment; toxicity; HDAC inhibitors; testicular degeneration; cytochrome p450; indole-3-carbinol; OS

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Citations

  • Sargeant, A. M. (2009). Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876

    APA Style (7th edition)

  • Sargeant, Aaron. Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer. 2009. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876.

    MLA Style (8th edition)

  • Sargeant, Aaron. "Preclinical Efficacy and Safety Evaluation of Novel Small-Molecule Targeted Agents for the Prevention and Treatment of Prostate Cancer." Doctoral dissertation, Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243948876

    Chicago Manual of Style (17th edition)

osu1243948876
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© 2009, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.