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UBC Theses and Dissertations

Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer Waterhouse, Dawn N.

Abstract

There are many drugs currently available for the treatment of aggressive breast cancer. These include anthracyclines, taxanes, alkylating agents, anti-metabolites, plant alkaloids, nucleoside analogues and anti-hormonal agents. Unfortunately, even armed with this impressive arsenal, there has been little ground gained in terms of disease free years or reduced mortality for what is an essentially incurable disease in the metastatic state. Clearly, we need to improve upon the therapies available for these patients. A key step toward this goal is the development of reproducible and relevant models in which newly developed drugs may be tested. This thesis outlines the characterisation of what is anticipated to be a powerful human xenograft model of aggressive breast cancer, that of the MDA435/LCC6 cell line. This cell line may be grown easily in vitro, as well as an ascitic or as a solid tumour in mice. In order to have a major impact in the field of breast cancer treatment, it will not suffice to develop yet another cytotoxic agent. Instead, we must turn to the newer technologies, including gene targeted therapies, which target the molecular root of the disease. This work includes the use of both free antisense oligonucleotides (ODN), as well as those formulated within a lipid carrier. These encapsulated ODN are retained in the circulation for a longer period of time, are less susceptible to the actions of nucleases, and due to pharmacokinetic and pharmacodistribution properties of the liposomal carrier, result in enhanced tumour cell uptake of the ODN. Finally, ODN, both free and liposome encapsulated, were administered to tumour bearing female SCID/Rag2m mice, either singly or in combination with a commonly used anticancer agent (doxorubicin). It is shown that ODN are capable of mediating the specific down-regulation of the target protein as well as impacting the rate of tumour growth. It is the intention of the author to demonstrate the necessity for not only good models and newly developed and specifically targeted therapeutic agents, but that we must also consider the use of combination strategies in the treatment of aggressive breast cancer such that current mortality statistics may be improved.

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