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Biological Activity of Pyrrole-Imidazole Polyamides in vivo

Citation

Szablowski, Jerzy Olgierd (2015) Biological Activity of Pyrrole-Imidazole Polyamides in vivo. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9Q23X6D. http://resolver.caltech.edu/CaltechTHESIS:05212015-030950854

Abstract

This thesis focuses on biological activity of pyrrole-imidazole polyamides in vivo. The work presented includes experiments underlining sequence selectivity of these compounds in living cells and potential methods to improve it. A large fraction of this thesis is devoted to activity of Py-Im in murine models of cancer. We investigated the pharmacokinetics and biodistribution of two compounds – targeted to 5'-WGGWCW-3' and 5'-WTWCGW-3' sequences – and characterized their activity by measuring their effects on tumor growth, gene expression in vivo and in tissue culture, and their effects on physiology of tumors. The initial theoretical studies suggested that a large fraction of genomic sites are bound by Py-Im polyamides non-specifically and experimental data shows that the programmed binding sequence is not a sole determinant of the patterns of gene regulation. Despite the likely presence of non-specific effects of Py-Im polyamides in living cells, in vivo administration of Py-Im polyamides resulted in tolerable host toxicity and anti-tumor activity. Py-Im polyamide targeted to Estrogen Receptor Response Element showed downregulation of ER-driven gene expression in tumor cells, while the compound targeted to hypoxia response element reduced vascularization of tumors and their growth rate, induced apoptosis of cells in hypoxic areas and reduced expression of proangiogenic and prometastatic factors. Further studies, showed that polyamides distributed to many of the tested tissues and their FITC-conjugates showed nuclear uptake. The gene expression effects were also present in murine tissues, such as liver and kidneys, indicating a potential for use for Py-Im polyamides in non-cancerous diseases.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Pyrrole-Imidazole Polyamide; hypoxia; estrogen; cancer; in-vivo; xenograft
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Bioengineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Dervan, Peter B.
Thesis Committee:
  • Arnold, Frances H. (chair)
  • Dervan, Peter B.
  • Mayo, Stephen L.
  • Phillips, Robert B.
Defense Date:1 May 2015
Funders:
Funding AgencyGrant Number
NIHGM027681
NIHGM051747
Record Number:CaltechTHESIS:05212015-030950854
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05212015-030950854
DOI:10.7907/Z9Q23X6D
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1158/1535-7163DOIArticle adapted for ch. 3: Activity of a Py–Im Polyamide Targeted to the Estrogen Response Element
http://dx.doi.org/10.1021/jm500964cDOIArticle adapted for ch. 4: Tumor Xenograft Uptake of a Pyrrole–Imidazole (Py-Im) Polyamide Varies as a Function of Cell Line Grafted
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8873
Collection:CaltechTHESIS
Deposited By: Jerzy Szablowski
Deposited On:29 Sep 2016 23:08
Last Modified:02 Oct 2017 19:39

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