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Antitumor activity of Py-Im polyamides

Citation

Yang, Fei (2014) Antitumor activity of Py-Im polyamides. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:07302013-124522822

Abstract

Molecules that inhibit DNA dependent processes are the most commonly used agents for the treatment of cancer. The genotoxicity associated with their mechanisms of action, unfortunately, make them extremely toxic to the patient and cancer cells alike. The work presented in this thesis outlines the development of Py-Im polyamides as non-genotoxic DNA-targeted antitumor molecules that interfere with RNA polymerase II elongation. We initially characterized the pharmacokinetic profiles of two hairpin polyamides to establish their bioavailability in the serum and tissues after a single administration. We next determined the molecular mechanism that contributes to toxicity of a hairpin polyamide in human prostate cancer cells in cell culture and we demonstrated antitumor effects of the compound against LNCaP xenografts in mice. Finally, we conducted animal toxicity experiments on 4 polyamides that vary on the gamma-turn with respect to the substitution of amino and acetamide groups at the alpha and beta positions. From this study we identified a second generation compound that retains antitumor activity with significantly reduce animal toxicity. This work sets the foundation for the development of Py-Im polyamides as DNA targeted therapeutics for the treatment of advanced prostate cancer.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Py-Im polyamides, prostate cancer, pharmacokinetics, animal toxicity
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Dervan, Peter B.
Thesis Committee:
  • Dervan, Peter B. (chair)
  • Hsieh-Wilson, Linda C. (chair)
  • Tirrell, David A.
  • Dougherty, Dennis A.
Defense Date:8 July 2013
Non-Caltech Author Email:fyang (AT) caltech.edu
Funders:
Funding AgencyGrant Number
National Institutes of Health (NIH)GM027681
Prostate Cancer FoundationUNSPECIFIED
Tobacco-Related Disease Research Program of the University of California18DT-0008
Record Number:CaltechTHESIS:07302013-124522822
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:07302013-124522822
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7920
Collection:CaltechTHESIS
Deposited By: Fei Yang
Deposited On:22 Jul 2014 16:54
Last Modified:20 Jan 2015 17:09

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