Antitumor activity of Py-Im polyamides


Autoria(s): Yang, Fei
Data(s)

2014

Resumo

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.

Formato

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

application/pdf

Identificador

http://thesis.library.caltech.edu/7920/37/Yang-Fei-2014-Thesis.pdf

http://thesis.library.caltech.edu/7920/4/Cover_page.pdf

http://thesis.library.caltech.edu/7920/1/Chapter%201.pdf

http://thesis.library.caltech.edu/7920/5/Chapter%203.pdf

http://thesis.library.caltech.edu/7920/5/Chapter%202.pdf

http://thesis.library.caltech.edu/7920/2/Chapter%204.pdf

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

Relação

http://resolver.caltech.edu/CaltechTHESIS:07302013-124522822

http://thesis.library.caltech.edu/7920/

Tipo

Thesis

NonPeerReviewed