Chemotherapeutic agents act by targeting rapidly dividing cancer cells. The full extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. In addition, the use of many anticancer drugs is limited by dose-limiting toxicities as well as the development of drug resistance. The work presented in this thesis aims to address the basic biology that underlies these issues through the development and application of chemical genomic tools to probe mechanisms of current and novel anticancer compounds. Chemical genomic screens in the yeast Saccharomyces cerevisiae have been used to successfully identify targets and pathways related to a compound’s mode of action. I applied these screens to examine the mode of action of potential anticancer drugs: a class of platinum-acridine compounds and the apoptosis-inducing compound elesclomol. By analogy to the yeast screens, I developed an RNAi-mediated chemical genomic screen in human cells which has the potential to reveal novel targets and drug mechanisms. This screen was applied to further understand doxorubicin’s mode of action. In parallel with the loss-of-function assays, our lab developed a human ORF overexpression screen in human cells. I applied this gain-of-function screen to identify those genes that, when overexpressed, are toxic to cells. Characterization of such genes that cause toxicity can provide insight into human diseases where gene amplification is prevalent.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/35790 |
| Date | 02 August 2013 |
| Creators | Cheung-Ong, Kahlin |
| Contributors | Nislow, Corey, Giaever, Guri |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis, Dataset |
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