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CR42-24, a Novel Colchicine Derivative, as a Therapy for Bladder Cancer

  • Author / Creator
    Clayton James Bell
  • Colchicine is an anti-mitotic drug that targets unpolymerized tubulin, and inhibits microtubule polymerization. It is primarily used to treat gout but has been investigated in numerous clinical trials to treat conditions such as leukemia (ALL), prostate cancer, and inflammatory diseases. However, due to its narrow therapeutic window colchicine has had limited clinical translation. Previously, our lab has designed and synthesized a novel colchicine derivative (CR42-24) with a more favorable pharmacological profile compared to colchicine. This was accomplished by designing a structure with an increased affinity for βIII tubulin. βIII tubulin is a β-tubulin isotype that is incorporated into tubulin dimers that make up microtubules. βIII is an excellent target for novel therapies as it has low expression in healthy tissue, is overexpressed in metastatic cancers, and is a clinical marker of poor prognosis. Using cell line screening we demonstrate that CR42-24 is highly toxic to a variety of cancer types with IC50 values at low nanomolar concentrations. More specifically CR42-24 is shown to be highly effective against bladder cancer. Current chemotherapy for bladder cancer is a combination of gemcitabine and cisplatin (gem/cis). Although marginally successful, many patients develop resistance to gem/cis leaving them with limited options for a second line therapy, thus development of alternative therapies is highly desired. Using in vitro and in vivo assays we demonstrate that CR42-24 is highly effective on BC cell lines and xenografts. We also show that CR42-24 is highly synergistic with other chemotherapies, thereby increasing its therapeutic potential. Through our studies we have shown that CR42-24 is effective in treating aggressive BC and thus may serve as an alternative or second line therapy.

  • Subjects / Keywords
  • Graduation date
    Fall 2018
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3513VB8K
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.