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Drug Resistance in Breast Cancer: Characterization of Rationally Designed Paclitaxel Analogs in Model Systems

  • Author / Creator
    St.George, Marc C
  • Breast cancer is a leading cause of cancer related deaths among women in the developed world. Treatment options for breast cancer include taxanes, which mediate cytotoxic effects by inducing microtubule polymerization which impedes cell division. Taxane resistant breast cancer is a mounting clinical problem, and can in part be explained by differential expression of -III tubulin and/or multidrug efflux pumps. I hypothesized that drugs traverse to the taxane active site through interactions at 275 and 278 residues (intermediate binding sites) within microtubule nanopores. I developed paclitaxel resistant SKBR-3 cell sub-lines, used synthesized paclitaxel analogs designed to interact with the suggested residues and attempted to dissect the progression of resistance by monitoring global microRNA profiles. Data did not favour interpretations on the hypothesized interactions with amino acid residues; evidence suggested that expression of -III tubulin alone does not explain drug resistance and a combination of mechanisms likely mediates resistance.

  • Subjects / Keywords
  • Graduation date
    2013-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R33N20P02
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Medical Sciences- Laboratory Medicine and Pathology
  • Supervisor / co-supervisor and their department(s)
    • Tuszynski, Jack (Oncology)
    • Damaraju, Sambasivarao (Medical Sciences - Laboratory Medicine and Pathology)
  • Examining committee members and their departments
    • Keelan, Monika (Medical Sciences - Laboratory Medicine and Pathology)
    • Goping, Ing Swie (Biochemistry)
    • Cass, Carol (Oncology)
    • Fahlman, Richard (Biochemisty)