xviii, 125 p. : ill. (some col.) / Since its approval by the FDA in 1978 cisplatin (cis-diamminedichloroplatinum(II)) has revolutionized the treatment of several cancer types, particularly testicular cancer which now has a cure rate greater than 90%. Following the example set by its success, a broad range of antitumor metallodrugs is being developed. One of the most promising of these drugs, currently in Phase Two of clinical trials, is the Ru-based NAMI-A (imadozolium trans -[tetrachloro(dimethylsulfoxide)(imidazole)ruthenate(III)]) which displays low systemic toxicity and strong antimetastatic activity. The majority of anticancer metallodrugs (including NAMI-A and cisplatin) can bind to DNA, which, in many cases, is an important therapeutic target. Much effort has gone into characterizing the DNA binding properties of anticancer metallodrugs. Less study has gone into characterizing the interaction of anticancer mellodrugs with RNA even though RNA is chemically similar to DNA and plays important roles in gene expression and regulation. Focusing on the extensively studied cisplatin, Chapter I covers both what is known about anticancer metallodrug-RNA binding and the information that can be gleaned from DNA binding and drug localization studies. Chapter II provides the details of a kinetic investigation of the in vitro binding of aquated cisplatin to an RNA sequence containing an internal loop derived from the core of the spliceosome, a related RNA hairpin, and the slower reacting DNA hairpin analog. Chapter III follows in cellulo studies with cisplatin-treated S. cerevisiae that demonstrate, using ICP-MS, differences in Pt accumulation in mRNA and rRNA. The effects of cisplatin treatment on S. cerevisiae cell growth and viability were investigated using clonogenic and morphologic assays. In Chapter IV the same protocols were applied in order to investigate Ru accumulation on RNA following S. cerevisiae treatment with NAMI-A. These in cellulo experiments were followed by in vitro binding studies that utilized MALDI-MS to compare Ru interactions with RNA and DNA oligonucleotides following treatment with NAMI-A under different solution conditions, finding enhanced binding in an acidic, reducing environment like that found in tumor tissue. Chapter V pulls together the knowledge gained so far and discusses questions for future investigation.
This dissertation includes both previously published and unpublished coauthored material. / Committee in charge: David Tyler, Chairperson;
Victoria DeRose, Advisor;
Darren Johnson, Member;
Andy Berglund, Member;
Alice Barkan, Outside Member
| Identifer | oai:union.ndltd.org:uoregon.edu/oai:scholarsbank.uoregon.edu:1794/11254 |
| Date | 03 1900 |
| Creators | Hostetter, Alethia A., 1981- |
| Publisher | University of Oregon |
| Source Sets | University of Oregon |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Relation | University of Oregon theses, Dept. of Chemistry, Ph. D., 2011; |
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