Molecular targeting of apoptosis for head and neck cancer therapy.
Published: 2006
Language: eng
Number of pages: 235
ISBN-13: 9780494219294
Description: Resistance to programmed cell death is a hallmark of cancer, and several genetic alterations in apoptosis are known to occur in head and neck cancers. These cancers account for &sim;3% of all new cancer cases in North America. The objective of this thesis is therefore to successfully modulate apoptosis for head and neck cancer therapy. Initially, an adenovirus expressing  BimS under a nasopharyngeal cancer (NPC)-specific promoter (ad5.oriP.BimS) was generated (Chapter 2). Ad5.oriP. BimS was highly potent, especially in combination with radiation therapy (RT). However, this therapy could not be effectively delivered in a systemic manner. The efficacy of Bcl-2 phosphorothioate antisense oligonucleotide (ASO) therapy was subsequently assessed due to its systemically-deliverable nature, and because, similar to ad5.oriP.BimS, it targeted the Bcl-2 family (Chapter 3). The efficacy of this therapeutic led our laboratory to attempt to begin clinical trials with Genta (Berkeley Heights, New Jersey), the owners of the legal rights to Bcl-2 ASO therapy (in the form of G3139/oblimersen sodium/Genasense). However, disappointing results of melanoma and myeloma clinical trials, along with changes in the Aventis/Genta partnership, have put G3139 clinical trials on hold. In order to identify novel (unpatented and unpublished) head and neck cancer-therapeutic small molecules, we therefore proceeded to perform a cell-based, and phenotype-driven high throughput screen (HTS) of the 1120-compound Prestwick (Prestwick Chemical Inc., Washington, D.C.) and the 1280-compound LOPAC1280 (Sigma-Aldrich Corporation, Saint Louis, Missouri) chemical libraries using a tetrazolium (MTS)-based assay (Chapter 4). This work identified benzethonium chloride as a novel systemically-deliverable apoptosis-inducing compound with broad-range antitumor activity. Furthermore, a second compound, alexidine dihydrochloride, was also identified as a head and neck cancer cell apoptosis-inducing drug lead (Chapter 5). Finally, because of the apparent efficacy of apoptosis-inducing therapies in NPC, the prognostic significance of Epstein-Barr virus (EBV), p53, Bcl-2, and survivin were assessed using immunohistochemistry (Chapter 6). EBV status was a strong independent predictor for overall patient survival, and was significantly associated with p53, Bcl-2, and nuclear survivin expression. This thesis has identified several novel head and neck cancer therapeutics with clinical potential, and provides a solid foundation for future head and neck cancer translational research.
Notes: Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0106.

Thesis (Ph.D.)--University of Toronto, 2006.

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