Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer
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 bee...
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ndltd-UBC-oai-circle.library.ubc.ca-2429-132292018-01-05T17:36:42Z Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer Waterhouse, Dawn N. 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. Medicine, Faculty of Pathology and Laboratory Medicine, Department of Graduate 2009-09-26 2009-09-26 2002 2002-05 Text Thesis/Dissertation http://hdl.handle.net/2429/13229 eng For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. 17425523 bytes application/pdf |
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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. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate |
author |
Waterhouse, Dawn N. |
spellingShingle |
Waterhouse, Dawn N. Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer |
author_facet |
Waterhouse, Dawn N. |
author_sort |
Waterhouse, Dawn N. |
title |
Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer |
title_short |
Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer |
title_full |
Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer |
title_fullStr |
Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer |
title_full_unstemmed |
Antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer |
title_sort |
antisense oligonucleotides as therapeutics for the treatment of aggressive breast cancer |
publishDate |
2009 |
url |
http://hdl.handle.net/2429/13229 |
work_keys_str_mv |
AT waterhousedawnn antisenseoligonucleotidesastherapeuticsforthetreatmentofaggressivebreastcancer |
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